Highlighting Progress Archives

Developing Models of Human Diseases - Expand and ensure access to animal models

Protease Inhibition Increases the Efficiency of Potential Gene Therapy for Glaucoma Treatment

March 14, 2018

Short-term exposure of the eye’s trabecular meshwork to a proteasome inhibitor increased the efficiency of gene delivery to specific cells in monkey organ-cultured anterior segments. These data suggest a strategy to improve ocular gene therapy for treatment of glaucoma.

Effective Vaccine for Prevention of Mycobacterium tuberculosis (Mtb)

March 14, 2018

Subcutaneous vaccination of rhesus macaques with a cytomegalovirus vector encoding Mtb inserts elicited and maintained T cell responses and reduced Mtb infection and disease by 68% in vaccinated versus control macaques after an intrabronchial challenge.

ORIP Participates in Rapid Zika Virus Model Development

February 28, 2017

Zika virus (ZIKV) is an emerging mosquito-borne virus that was first detected in Brazil in 2015 and has since become a global pandemic. The World Health Association declared the ZIKV pandemic a public health emergency in February 2016. Because there is little known to date about the virus, there is an urgent need for animal models to better understand the pathology of transmission and to test therapeutic interventions.

ORIP has a particular interest in developing and characterizing animal models that can be used to study basic aspects of ZIKV infection and pathogenesis and has responded to the global ZIKV pandemic. ORIP has awarded several grants following their notice to participate in the funding opportunity announcement (FOA) “Rapid Assessment of Zika Virus (ZIKV) Complications (PAR-16-106).” This FOA promotes ongoing submission, review, and award of applications that address issues related to this emerging pathogen as a public health crisis. ORIP meets with the other 8 participating Institutes and Centers (NICHD, NIAID, NIDCR, NINDS, NEI, NIBIB, NIMH and NHLBI) to discuss best practices and implementation of continuous submission of applications.

Developing Models of Human Diseases - Continue to develop and enhance human disease models and research-related resource programs to advance medical research

Slow Delivery Immunization Enhances HIV Neutralizing Antibody (nAb) and Germinal Center (GC) Responses via Modulation of Immunodominance

June 13, 2019

Investigators determined that slow delivery immunization methods of HIV envelope (Env) protein vaccine to rhesus macaques resulted in robust T follicular helper cell responses and GC B cells with improved Env-binding. The GCs correlated with the development of higher titers of autologous nAbs. Slow delivery-immunized animals also demonstrated a more diverse set of epitopes. Thus, alternative immunization strategies can enhance nAb development by altering GCs and modulating the immunodominance of non-neutralizing epitopes.

Colonic Inflammation Affects Myenteric Alpha-Synuclein in Nonhuman Primates

June 13, 2019

Parkinson’s disease (PD) patients frequently present gastrointestinal dysfunction that often predates the onset of motor symptoms. The presynaptic protein alpha-synuclein (α-syn) undergoes pathological changes, including phosphorylation and aggregation, leading to the formation of Lewy bodies. Using a marmoset model of colitis, investigators demonstrated that the colonic mesenteric ganglia had significantly increased expression of inflammatory markers, oxidative stress, and decreased expression of α-syn, as compared to normal, healthy controls. Future evaluation of the vagus nerve and brain of marmosets with colitis are needed to assess the contribution of colitis-induced α-syn pathology to PD-like pathology in the brain.

Chronic Alcohol Drinking Slows Brain Development in Adolescent and Young Adult Nonhuman Primates (NHPs)

June 13, 2019

Alcohol abuse during late adolescence/early adulthood is a risk factor for alcohol dependence. In this longitudinal study, an NHP model of alcohol self-administration and in vivo MRI were used to quantify the impact of chronic alcohol use. Chronic alcohol self-intoxication reduced the growth rate of brain, cerebral white matter, and subcortical thalamus. Heavy drinking during the transition to adulthood significantly impacts critical areas of sensory motor integration, concomitant with a decrease in cortical white matter, which is linked to the continuation of alcohol use disorder.
Oregon NPRC (99 words)

Tuberculosis (TB) Exacerbates HIV-1 Infection through IL-10/STAT3-Dependent Tunneling Nanotube Formation in Macrophages

June 13, 2019

The mechanisms by which TB exacerbates HIV-1 pathogenesis are not well known. Investigators used in vitro, ex vivo, and nonhuman primate (NHP) models to examine TB impact on HIV. TB-induced macrophages overproduce HIV-1, promote HIV-1 spread through tunneling nanotubes (TNTs) between macrophages via IL-10/STAT3 signaling, and accumulate in TB/HIV co-infected humans and NHPs. The study has implications for exploring potential TB/AIDS therapeutics that target inhibition of TNT formation.

mGAP: The Macaque Genotype and Phenotype Resource, A Framework For Accessing and Interpreting Macaque Variant Data, and Identifying New Models Of Human Disease

June 13, 2019

The mGAP resource is the first public website providing searchable, annotated macaque variant data and includes a catalog of high confidence variants derived from whole genome sequence from hundreds of rhesus macaques processed in a consistent manner. A custom pipeline was developed to enable annotation of the macaque variants, leveraging human data sources that include regulatory elements, known disease- or phenotype-associated variants, predicted impact, and sequence conservation. The mGAP resource (https://mgap.ohsu.edu) presents an unprecedented opportunity to investigate potential genetic associations with currently characterized disease models and to uncover new macaque models based on parallels with human risk alleles.

Fluorescent Light Incites a Conserved Immune and Inflammatory Genetic Response within Vertebrate Organs (Danio rerio, Oryzias latipes and Mus musculus)

May 2, 2019

Fluorescent light (FL) has become a common artificial light source under which animals, including humans, spend increasing amounts of time. Although the solar spectrum is quite dissimilar in both wavelengths and intensities, the genetic consequences of FL exposure have not been investigated. Comparative RNA-Seq studies establish expression patterns within skin, brain, and liver for Danio rerio (zebrafish), Oryzias latipes (medaka), and the hairless mouse (Mus musculus) after exposure to FL. The skin and brain of the three animal species as well as the liver of both fish models all exhibit increased inflammation and immune responses; however, the mouse liver suppressed the same pathways. Overall, the conserved nature of the genetic responses observed after FL exposure, among fishes and a mammal, suggest the presence of light responsive genetic circuitry deeply embedded in the vertebrate genome.

Modeling Diverse Responses to Filled and Outline Shapes in Macaque V4

May 2, 2019

Using the macaque model, investigators studied neurons in the visual cortex area V4 to determine critical aspects for identifying an object’s shape; object fill versus outline versions served as stimuli. Neurons in V4 responded differently to the filled and outline shapes, suggesting boundary orientation and interior surface information are maintained at the midlevel visual representation and object fill is important for recognition and perception.

Autologous Grafting of Cryopreserved Prepubertal Rhesus Testis Produces Sperm and Offspring

May 2, 2019

Investigators grafted cryopreserved testicular tissue from castrated pubertal male macaques under the skin of the animal’s back or scrotum. The autologous grafts matured and produced testosterone and sperm that were capable of fertilizing oocytes, resulting in one successful pregnancy. The results support a possible approach to preserving human fertility in boys undergoing treatment for childhood cancers.

Adeno-Associated Virus (AAV) Delivery of Anti-HIV Monoclonal Antibodies Can Drive Long-Term Virologic Suppression

May 2, 2019

Macaques chronically infected with simian-human immunodeficiency virus (SHIV) were treated with a genetically-modified AAV to induce endogenous production of broadly neutralizing antibodies (bnAbs) against SHIV. Macaques that produced the bnAbs demonstrated long-term suppression of viremia in the absence of anti-retroviral therapy; however, two macaques developed a foreign body reaction to the bnAbs. The study provides proof-of-concept of a functional cure through the AAV approach, but host generation of anti-antibodies limits effectiveness and needs to be addressed in future studies.

Robust CRISPR/Cas9-mediated tissue-specific mutagenesis reveals gene redundancy and perdurance in Drosophila

April 29, 2019

Investigators have developed in Drosophila a CRISPR-mediated tissue-restricted mutagenesis method, called CRISPR-TRiM, for ablating gene function in a tissue-specific manner by using multiple guide RNAs and enhancer-driven Cas9. This method reduces the cytotoxicity of Ca9 protein and generates persistent tissue-specific gene knockout. This study provides a versatile gene editing tool for somatic cell mutagenesis in many human disease-related biological processes.

Robust CRISPR/Cas9-Mediated Tissue-Specific Mutagenesis Reveals Gene Redundancy and Perdurance in Drosophila. Poe AR et al. Genetics. (2019) 211(2):459-472. doi: 10.1534/genetics.118.301736).

Large-scale discovery of mouse transgenic integration sites reveals frequent structural variation and insertional mutagenesis

April 29, 2019

Transgenic mouse models have had an enormous impact on biomedical research. Generated through the random integration of DNA fragments, transgenesis can lead to insertional mutagenesis. Researchers report the first large-scale analysis of transgene insertion sites from 40 highly used transgenic mouse lines. Evidence suggests that the transgenes disrupt the coding sequence of endogenous genes in half of the lines, frequently involving large deletions and/or structural variations. The data highlights the need for careful characterization of each line to assure interpretable and reproducible experiments.

(R24OD011190, U42OD011185, UM1OD023222, U42OD010921)

Genome Res. 2019 Mar;29(3):494-505 https://genome.cshlp.org/content/29/3/494.long Large-scale discovery of mouse transgenic integration sites reveals frequent structural variation and insertional mutagenesis, Leslie O. Goodwin, Erik Splinter, Tiffany L. Davis, Rachel Urban, Hao He, Robert E. Braun, Elissa J. Chesler, Vivek Kumar, Max van Min, Juliet Ndukum, Vivek M. Philip, Laura G. Reinholdt, Karen Svenson, Jacqueline K. White, Michael Sasner, Cathleen Lutz and Stephen A. Murray

Regulation of T cell expansion by antigen presentation dynamics

April 29, 2019

Antigen-specific T cells proliferate multiple times during an immune reaction to fight against disease. This expansion of T cells must be carefully regulated to ensure an effective defense while avoiding autoimmunity. Mathematical modeling has found that exponentially increasing antigen doses can achieve a nearly optimized response, showing that the dynamics of presented antigen is a key regulator of both the size and specificity of the adaptive immune response. These results could play an important role in optimizing vaccination protocols.

(R01-OD011095, Modeling Viral and T Lymphocyte Dynamics, Perelson AS, Los Alamos National Security)

Proc Natl Acad Sci U S A. 2019 Mar 26;116(13):5914-5919. doi: 10.1073/pnas.1812800116. Epub 2019 Mar 8. Regulation of T cell expansion by antigen presentation dynamics. Mayer A, Zhang Y, Perelson AS, Wingreen NS.

Cortical phase-amplitude coupling in a progressive model of parkinsonism in nonhuman primates (NHPs)

April 29, 2019

Investigators examined electrocorticogram recordings in an NHP model of progressive parkinsonism. Increased abnormal phase-amplitude coupling (PAC) was observed in NHPs with advanced parkinsonism. The observed coupling in the awake parkinsonian state decreased with levodopa treatment. The data suggest the disturbances underlying PAC may not be essential for the development of motor symptoms, but increased PAC does correlate with disease severity. The late changes in PAC suggests this would not be a useful biomarker for detecting early Parkinson’s disease.

Single-cell sequencing of primate preimplantation embryos reveals chromosome elimination via cellular fragmentation and blastomere exclusion

April 29, 2019

Investigators demonstrated that aneuploidy and micronucleation frequency is conserved between humans and macaques, and that fragments encapsulate whole or partial chromosomes lost from blastomeres. These chromosome-containing cellular fragments (CCFs) may be maternally or paternally derived, display double-stranded DNA breaks, and were associated with multipolar divisions at the zygote or two-cell stage. CCFs and nondividing aneuploid blastomeres with extensive DNA damage were not incorporated into blastocysts. These findings suggest embryos encapsulate chromosomal errors and select against highly aneuploid blastomeres to overcome chromosome instability during preimplantation development.

Chronic ethanol drinking increases during the luteal menstrual cycle phase in rhesus monkeys (RM): implication of progesterone and related neurosteroids

April 29, 2019

Using a RM model of ethanol self-administration, investigators showed that females drank more ethanol during the luteal phase, when progesterone and select neuroactive steroids (pregnanolone and 3α,5α-tetrahydroprogesterone) are elevated. These findings suggest that normal menstrual cycle fluctuations in progesterone can modulate alcohol intake and may be involved in sex-related risk factors for alcohol consumption.

Evolutionarily conserved Tbx5-Wnt2/2b pathway orchestrates cardiopulmonary development.

April 29, 2019

The transcription factor TBX5 has been involved in congenital heart defects; however, few direct targets of TBX5 in cardiac morphogenesis have been identified. Scientists have demonstrated that TBX5 directly regulates canonical Wnt ligands required for initiation of lung development (in mice and frogs). Lung endoderm forms a Hedgehog signaling source required for morphogenesis of both the lungs and the cardiac inflow septum. This research expands the role of TBX5 to include a non–cell-autonomous component for atrial septation. It was found that the mesoderm–endoderm–mesoderm signaling loop initiated by TBX5 is evolutionarily conserved from amphibians to mammals. Findings suggests that the evolutionary origin of lungs may have involved the recruitment of cardiac TBX5.

A chromosome-scale assembly of the axolotl genome

April 29, 2019

The axolotl (Ambystoma mexicanum) provides critical models for studying regeneration, evolution, and development. However, its large genome (near ten times larger than the human) presents a formidable barrier to genetic analyses. A new assembly encompasses 94% of annotated gene models on chromosomal scaffolds. The assembly’s utility was demonstrated by resolving genome-wide orthologues between the axolotl and other vertebrates, identifying the footprints of historical introgression events that occurred during the development of axolotl genetic stocks, and precisely mapping several phenotypes including a large deletion underlying the cardiac mutant (thus providing a new model of human disease). This chromosome-scale assembly will greatly facilitate studies of the axolotl in biological research, especially regenerative medicine.

Improvement of in vitro and early in utero porcine clone development after somatic donor cells are cultured under hypoxia

April 29, 2019

Genetically engineered pigs serve as excellent biomedical research models. To date, the most reliable way to generate genetically engineered pigs is via somatic cell nuclear transfer; however, the efficiency of cloning in pigs is low. Pilot studies suggest that clones from donor cells (somatic cells such as fibroblasts) cultured under hypoxic conditions (that resembles embryonic-like metabolic conditions) are more developmentally competent and this may be due to improved nuclear reprogramming during somatic cell nuclear transfer.

A longitudinal assessment of host-microbe-parasite interactions resolves the zebrafish gut microbiome’s link to Pseudocapillaria tomentosa infection and pathology

April 29, 2019

Because helminth parasites represent a significant threat to the health of human and animal populations, there is a growing need for tools to treat, diagnose, and prevent these infections. As gut microbiome components may interact with parasites to influence their success in the gut, studying these interactions may shed light into how the microbiome, host pathology, and parasite burden covary during infection and may uncover novel putative methods of disrupting parasite success. Studies using the intestinal helminths of zebrafish, Pseudocapillaria tomentosa, and the gut microbiome demonstrated that P. tomentosa infection disrupts zebrafish gut microbiome composition and identifies potential interactions between the gut microbiota and parasite success.

Vaccine protection against SIVmac239 acquisition

April 29, 2019

A vaccine regimen, which included a replication-competent herpesvirus engineered to contain a near-full-length simian immunodeficiency virus (SIV) genome expressing all nine SIV gene products was tested in rhesus macaques. Vaccinated macaques were significantly protected against acquisition of SIVmac239, a difficult to neutralize virus strain, following repeated marginal dose intravenous challenges over a 4-month period. Defining the critical components necessary for eliciting protective immunity and evaluating the breadth of the protection against a variety of strains are needed to explore how this approach may be extended to human use.

Rescue of rhesus macaques from the lethality of aerosolized ricin toxin

April 29, 2019

The therapeutic potential of a humanized monoclonal antibody against an immunodominant epitope on ricin’s enzymatic A chain was investigated in rhesus macaques. This is the first demonstration in nonhuman primates that the lethal effects of inhalational exposure to ricin, a potential bioweapon, can be negated by a drug candidate.

Differentiation of primate primordial germ cell-like cells following transplantation into the adult gonadal niche

April 29, 2019

Transplantation of aggregates containing rhesus primordial germ cell-like cells (rPGCLCs) from induced pluripotent stem cells into mouse and nonhuman primate testicles overcomes a major bottleneck in rPGCLC differentiation. The findings suggest that immature rPGCLCs once transplanted into an adult gonadal niche commit to differentiate towards late rhesus primordial germ cells that initiate epigenetic reprogramming but do not complete the conversion into spermatogonia.

Stage-specific modulation of antimüllerian hormone (AMH) promotes primate follicular development and oocyte maturation in the matrix-free three-dimensional culture

April 29, 2019

Using a rhesus macaque model, investigators cultured primary and secondary follicles in a matrix-free system to determine whether follicular growth and oocyte maturation would be improved by the addition of AMH. AMH supplementation at the preantral stage and depletion at the antral stage enhanced primate follicular development and oocyte competence in vitro. The improved embryonic development supports in vitro follicle maturation as a potential approach for fertility preservation.

Mucosal T helper 17 (Th17) and T regulatory (Treg) cell homeostasis correlates with acute simian immunodeficiency virus (SIV) viremia and responsiveness to antiretroviral therapy (ART) in macaques

April 29, 2019

Researchers investigated the relationship between the mucosal Th17 and Treg cell ratio in response to acute SIV viremia and combination ART (cART) in rhesus macaques. Th17/Treg ratios decreased during acute SIV infection and were not restored during cART; this corresponded to increased gut immune activation, markers of microbial translocation, and T-cell exhaustion. A more balanced mucosal Th17/Treg ratio at the time of cART initiation was indicative of a better virologic response to cART and higher peripheral CD4 counts. The results suggest mucosal Th17 and Treg homeostasis influences acute viremia and the response to cART.

Identification and functional characterization of a novel Fc gamma (ɣ)-binding glycoprotein in rhesus cytomegalovirus (CMV)

April 29, 2019

Investigators used gene mapping and a novel cell-based reporter assay system to characterize a rhesus CMV encoded immunoglobulin G (IgG)-Fcɣ binding glycoprotein, which acts as a potent antagonist of rhesus Fcγ receptor activation. This viral Fcγ receptor is not required to overcome anti-CMV immunity in establishing secondary infections. Future studies of the in vivo consequences of CMV evasion from IgG responses will be explored in nonhuman primate models.

Effects of Maternal Western‐Style Diet (WSD) On Amniotic Fluid Volume (AFV) And Amnion VEGF Profiles in A Nonhuman Primate (NHP) Model

December 10, 2018

The effects of maternal WSD on AFV and potential changes in vascular endothelial growth factor (VEGF) and soluble VEGF receptor 1 expression profiles were investigated in an NHP model. The results suggest that a maternal WSD may exert differential effects on the amnion depending on maternal sensitivity to the WSD. In sensitive NHPs, WSD leads to maternal obesity and increased plasma insulin levels without an impact on AFV or changes in the VEGF pathway. The investigators noted a potential association between reduction in amniotic fluid VEGF levels and development of resistance to certain adverse effects of WSD.

114 Words (Oregon NPRC, P51OD011092), SHERI

Effects of Immediate or Delayed Estradiol on Behavior in Old Menopausal Macaques on Obesogenic Diet

December 10, 2018

Hysterectomized macaques were fed a western-style diet (WSD) and treated with placebo or estradiol (E) either immediately after hysterectomy or after a 2-year delay to determine the impact of E treatment and WSD on behaviors. WSD increased anxiety-behaviors in all macaques, and placebo-control macaques exhibited less activity compared to E-treated macaques. The investigators conclude that WSD promoted increased consummatory, sedentary, and anxiety-type behaviors, whereas immediately after hysterectomy promoted activity.

84 Words (Oregon NPRC, P51OD011092), SHERI

Antibody and TLR7 Agonist Delay Viral Rebound in SHIV-Infected Monkeys

December 10, 2018

Combination of antibody treatment and innate immune stimulation can effectively delay viral rebound in SHIV-infected rhesus monkeys. Investigators found that administration of a human immunodeficiency virus (HIV) antibody together with an innate immunity-related Toll-like receptor 7 (TLR7) agonist during antiretroviral therapy (ART) delayed viral rebound from viral reservoir following discontinuation of ART in simian-human immunodeficiency virus (SHIV)-infected monkeys. The study suggests a possible strategy to cure HIV infection by effectively targeting the viral reservoir with a combination of immunotherapy and innate immune activation.

93 Words (R01 OD024917, PI: Barouch, Dan H; Virgin, Herbert W) SIGE

Early High-Fat Diet (HFD) Exposure Causes Dysregulation of the Orexin and Dopamine Neuronal Populations in Nonhuman Primates (NHPs)

December 10, 2018

Maternal obesity and consumption of an HFD during pregnancy results in an increased risk for the offspring to develop obesity in adolescence. Investigators examined the impact of in utero and neonatal HFD exposure on the dopaminergic control of pleasure-seeking feeding pathways in an NHP model. Prolonged early exposure to HFD resulted in alterations at several levels in the dopaminergic circuits regulating reward.

80 Words (Oregon NPRC, P51OD011092), SHERI

Pre-Existing SIV Infection Increases Susceptibility to Tuberculosis in Mauritian Cynomolgus Macaques (MCM)

December 10, 2018

Researchers developed an MCM co-infection model of Mycobacterium tuberculosis (M.tb) and simian immunodeficiency virus (SIV), a human immunodeficiency virus (HIV) surrogate, to investigate mechanisms by which HIV impairs host resistance to M.tb infection. Tuberculosis (TB) progression was monitored by clinical parameters, bacilli cultures and positron emission tomography/computed tomography imaging. Rapidly progressive TB was observed in the co-infection model with significant increases in TB granulomas in SIV-infected MCMs, suggesting SIV impairs the ability of animals to contain M.tb dissemination.

90 Words (Wisconsin NPRC, P51OD011106), SHERI

Charting the Onset of Parkinson-Like Motor and Non-Motor Symptoms in Nonhuman Primate Model (NHP) Of Parkinson’s Disease (PD)

December 10, 2018

PD is a multisystem disorder involving motor and non-motor symptoms. Using a marmoset model of PD , investigators analyzed cognitive deficits, daytime and nighttime tremors as well as sleep and circadian rhythm disturbances, which similar to those observed in PD patients. These symptoms need to be considered in translating effective new therapeutics for PD.

79 Words (Southwest NPRC, P51OD011133), SHERI

Ovarian Estradiol Supports Sexual Behavior but Not Energy Homeostasis in Female Marmoset Monkeys

December 10, 2018

Investigators used a nonhuman primate model to determine if ovarian estradiol regulates body weight, adiposity, energy balance, physical activity, glucose-insulin homeodynamics, and lipid metabolism, as observed in rodents. Ablation of ovarian estradiol negatively impacted sexual behavior, but the metabolic pathways were largely unaffected. The results suggest primates evolved metabolic control systems that are not as sensitive to estradiol regulation.

72 Words (Wisconsin NPRC, P51OD011106), SHERI

Early Antiretroviral Therapy (ART) Limits SIV Reservoir Establishment to Delay or Prevent Post-Treatment Viral Rebound

December 10, 2018

Early administration of combination ART (cART) in rhesus macaques infected with pathogenic simian immunodeficiency virus (SIV) prevented viral rebound once cART was discontinued. Timing was critical as this was observed when cART was initiated within 5 days of infection, but a delay of 1-2 days in cART administration was not protective. These results suggest that the early SIV reservoir is limited in durability and that effective blockade of viral replication and spread during a critical time window may result in reduction, and potentially loss, of rebound-competent virus.

102 Words (Oregon NPRC, P51OD011092), SHERI

In vivo imaging of inflammation and oxidative stress in a nonhuman primate (NHP) model of cardiac sympathetic neurodegeneration

October 24, 2018

Positron emission tomography (PET) imagining with specific radioligands was used to follow cardiac innervation, inflammation and oxidative stress in an NHP model of cardiac sympathetic neurodegeneration. The radioligands may be useful biomarkers in detecting cardiac disease and evaluating new therapies for cardiac neurodegeneration and neuroprotection.

SNARE Complex-associated proteins in the lateral amygdala of Macaca mullatta following long-term ethanol drinking

October 24, 2018

Examinations of the brains of macaques after long-term ethanol self-administration demonstrated alterations in SNARE and SNARE-associated proteins in the basal amygdala, a brain region involved in aversive and reward-seeking behaviors. Sex differences were also observed. The authors propose that SNARE components may represent heritable phenotypes associated with ethanol drinking behavior.

Human embryonic stem cell-derived cardiomyocytes (hESC – CMs) restore function in infarcted hearts of non-human primates

October 24, 2018

Transplantation of ~750 million cryopreserved hESC – CMs enhanced cardiac function in macaques that had previously experienced a myocardial infarction. Grafts formed electromechanical junctions within the host heart and improved ventricular ejection volume. These data demonstrate the ability of stem cells to remuscularize the heart and improve ventricular function.

Experimental Zika Virus (ZIKV) Infection in the Pregnant Common Marmoset Induces Spontaneous Fetal Loss and Neurodevelopmental Abnormalities

October 24, 2018

Marmosets infected with the Brazilian strain of ZIKV during early gestation exhibited asymptomatic seroconversion and persistent viremia. Spontaneous pregnancy loss was observed 16–18 days post-infection and accompanied by active placental viral replication and fetal neurocellular disorganization, a similar finding to humans. These results suggest a key role for the placenta in fetal infection and demonstrate the utility of marmoset model.

Anti-HIV IgM protects against mucosal SHIV transmission

October 24, 2018

Investigators demonstrated intra-rectal immunization with a monoclonal IgM inhibited mucosal transmission of simian immunodeficiency virus in a macaque HIV/AIDS model. This proof-of-concept study holds promise for HIV prevention and vaccine strategies.

Maternal diet, metabolic state, and inflammatory response exert unique and long-lasting influences on offspring behavior in non-human primates

October 24, 2018

The effects of maternal diet and metabolic state on gestational inflammatory environment and subsequent offspring behavior was explored in a macaque model. Results suggest that maternal diet, adiposity, and macrophage-derived chemokines influence offspring emotional and behavioral dysregulation.

Fair-Minded Rats Pay Helpers with Food

March 14, 2018

‘Rub my back and I’ll give you a sweet’ — rats engage in this kind of trade, suggesting that cooperation among animals is more widespread than thought.

Norway rats are known to exchange food and grooming sessions. But investigators wanted to know whether the animals would swap dissimilar resources, such as food in exchange for grooming.

Test animals were generally eager to groom the partners who had gifted them food, and vice versa. But test animals tended to be stingy with favors towards a partner that had given them nothing.

Support of Technologies

March 14, 2018

ORIP supports high-quality animal models, and specialized animal research facilities, to meet the needs of biomedical researchers. Through the small business program, ORIP is funding research aimed at developing new technologies to improve those animal models and facilities.

Examples of ORIP supported new technologies include the Collagen Hybridizing Peptide, that provides a versatile tool for developmental biology research and histology-based disease diagnosis, staging, and therapeutic screening of collagen, and the Embryo Cradle device used to grow and study the behavior of human gastric epithelial spheroids (organoids) generated from adult tissue samples.

Humanized Mice Advance Research

March 14, 2018

The Center for Humanized Mice Development (University of Nebraska Medical Center) is developing improved animal models as resources to study human immunity, human-specific infections, vaccines, and human-specific drug interactions.

A new mouse model with human liver enzymes provided the opportunity to test therapeutic activity and toxicity of anti-retroviral drug metabolites.

Humanized mice were also used to test new eradication strategies using CRIPR/cas9 excision and long-acting, slow effective release therapies.

A Whole-Animal Platform for Development of New High-Efficiency and Low-Toxicity Drugs

March 14, 2018

Scientists from one of the Pilot Centers for Precision Disease Modeling funded by ORIP (Icahn School of Medicine at Mount Sinai, NY), are developing drug-based therapeutics that target abnormal networks. They reported discovery of a new class of “tumor-calibrated inhibitors” with strongly improved therapeutic index in fly and human cancer xenograft models. This approach may also prove useful in drug development strategies outside of oncology, such as neural and cardiovascular diseases.

Authors published a Concept article introducing a new DREAM Challenge to help realize the promise of their rational polypharmacology approach.

Zika Virus (ZIKV) Infection in Pregnant Rhesus Macaques Causes Placental Dysfunction

March 14, 2018

Pregnant rhesus macaques infected subcutaneously with ZIKV demonstrated outwardly normal fetal growth, but persistent fetal-placenta-maternal infection and adverse effects on placental oxygen reserve and decreased oxygen permeability. Uteroplacental pathology that affects oxygen delivery to the fetus may be involved in Congenital Zika Syndrome.

Regulation of Tissue Expansion in Drosophila Intestine

February 6, 2018

Scientists at Indiana University are delineating the molecular and cellular activities of the conserved regenerative pathway, Lin-28, that is involved in developmental timing and regulates the self-renewal of stem cells.  Essential details about this pathway, its mRNA targets, mechanism of action and regulation are currently unknown. In a recent study, scientists reported that fragile X mental retardation protein (FMRP) functions via LIN-28 to control the behavior of intestine progenitor cells in response to nutrition. Since the loss of FMRP in humans causes fragile X syndrome (FXS), the study raises the possibility that defective adaptive growth might be causing pathological conditions that are affecting FXS patients.

Hypothalamic Production of Estradiol is Essential for Induction of the Luteinizing Hormone (LH) Surge and Ovulation in Nonhuman Primates (NHPs)

February 6, 2018

Exogenous estradiol treatment cannot elicit an LH surge in ovariectomized NHPs whose endogenous estradiol is suppressed with an aromatase inhibitor. These results indicate the obligatory role of hypothalamic estradiol production in stimulating the LH surge and subsequent ovulation.

Inhibition of tryptophan Catabolism Augments Immune-mediated Control of Mycobacterium tuberculosis (Mtb)

February 6, 2018

Tryptophan metabolites suppress host immunity and Mtb induces expression of indoleamine 2,3-dioxygenase (IDO) enzyme, which is involved in tryptophan catabolism. Suppression of the IDO enzyme in Mtb-infected macaques reduced bacterial burden, pathology, and clinical signs of tuberculous (TB) suggesting inhibition of IDO has potential for an effective and clinically relevant host-directed therapy for TB.

Targeting the HIV/AIDS Viral Reservoir

February 6, 2018

Studies in antiretroviral-treated simian immunodeficiency virus (SIV)-infected rhesus macaques indicate a specific group of CD4+ memory T cells harbors SIV DNA that is replication-competent and potentially infectious; these T cells are located in multiple tissues and express cytotoxic T-lymphocyte-associated protein 4 (CTLA4), but not programmed cell death protein 1 (PD1). Therapies designed to eliminate HIV from infected patients should consider CTLA4 as a target.

Aged Rhesus Macaques as a Model for Alzheimer's Disease

January 10, 2018

Detailed immunoelectron microscopy and biochemical assays of aging rhesus macaque brains indicate a disease progression that recapitulates Alzheimer’s disease in humans suggesting the rhesus would be an appropriate model for Alzheimer's disease. 

New World Monkey Model Reproduces Key Features of Human Zika Virus (ZIKV) Infection

January 10, 2018

Similarities between ZIKV infection of marmoset monkeys and humans include: asymptomatic in most cases, persistence of ZIKV in bodily fluids, and generation of neutralizing antibodies. Re-challenge of the monkeys with a Brazilian strain of ZIKV resulted in protection from re-infection. Results support use of this marmoset as a model for the human disease.

A Mutant Mouse Centralized Repository for Researchers

June 15, 2017

The Mutant Mouse Resource and Research Center (MMRRC) is a program of the National Institutes of Health (NIH) that strives to expand and ensure access to well-defined, high-quality rodent models for biomedical research. Supported by ORIP’s Division of Comparative Medicine and aligned with ORIP’s 2016‒2020 Strategic Plan to develop novel models of human diseases to study, understand, and eventually cure complex diseases, the MMRRC consists of four centers (at the University of California at Davis, University of Missouri, University of North Carolina at Chapel Hill, and The Jackson Laboratory) that operate as a central repository to accept, cryopreserve, maintain, and distribute mutant mouse strains. By accepting reagents from researchers, the MMRRC promotes an environment of responsible conduct of research, where scientists are obliged to share their resources with each other, which minimizes costs and time associated with the distribution of reagents. From 2010 to April 2017, the MMRRC received more than 8,633 orders from investigators. The MMRRC saves scientists time and costly efforts of having to house, breed, rederive, and characterize mice and conduct duplicative studies due to unexpected phenotypes and experimental variability. The MMRRC now offers next-generation gene sequencing technology of gut microbiota in mice to better equip researchers to conduct reliable and reproducible science, and to avoid unexpected study results. In 2016, the NIH funded the second phase of the newly developed Common Fund’s Knockout Mouse Project (KOMP 2) to make more than 3,000 new genetic knockout mice available through the MMRRC program

A Four Dimensional Atlas of Dynamic Embryo Imaging

June 15, 2017

The complexity of the neurological circuitry and development in higher ordered vertebrates has hindered the ability to dynamically capture single cells, the entire nervous system, and the overall process of development. The invertebrate nematode (roundworm) Caenorhabditis elegans (C. elegans) is an ideal organism for modeling neurodevelopment because of its simplistic nervous system. C. elegans is used to answer important research questions regarding how cells function and the role of certain genes. Scientists have grappled with modeling embryo development in this organism because of rapid embryonic movement, muscle twitching, and the lack of spatial resolution commonly observed by microscopy. These challenges result in poor image quality and lowered dimensionality. Despite certain technical enhancements in microscopic imaging, the morphological changes in the embryo hamper the ability to view individual cells. Genetically engineered C. elegans that express fluorescent markers are being used to easily view individual cells and dynamically track the stages of development. The National Institutes of Health supported a research collaboration to create a novel four dimensional (4D) atlas of embryogenesis and neurodevelopment in C. elegans1 through a project called Worm Global Understanding in Dynamic Embryonic Systems (WormGUIDES).2 This atlas is the first 4D embryo atlas of nuclear positions of all cells of the worm embryo. Captured images representing the entire organism can be computationally “untwisted.”1 Collected images allow scientists to track cellular components and to combine data from multiple C. elegans to model time-lapse development. Available through a mobile or desktop application3, WormGUIDES develops an interactive tool that presents the 4D atlas of single cells and their coordinated movement, gene expression, and overall development. Users can access information regarding cellular positioning and neuron growth during embryogenesis. WormGUIDES provides a reference tool and may assist in identifying therapeutic targets of disease.

 

References

1Christensen RP, Bokinsky A, Santella A, Wu Y, Marquina-Solis J, Guo M, Kovacevic I, Kumar A, Winter PW, Tashakkori N, McCreedy E, Liu H, McAuliffe M, Mohler W, Colón-Ramos DA, Boa Z, Shroff H. Untwisting the Caenorhabditis elegans embryo. eLife. 2015(4):e10070

2Santella A, Catena R, Kovacevic I, Shah P, Yu Z, Marquina-Solis J, Kumar A, Wu Y, Schaff J, Colón-Ramos, DA, Shroff H, Mohler WA, Bao Z. WormGUIDES: an interactive single cell developmental atlas and tool for collaborative multidimensional data exploration. BMC Bioinformatics. 2015 June 9(16):189.  

3http://www.wormguides.org/home

Pilot Centers for Precision Modeling

February 28, 2017

Recent scientific and technological advances, such as affordable whole genome sequencing and molecular profiling, enable us to study the genetics and pathogenesis of many human diseases. The goal of using this information is to provide patient-precise treatments based on their unique genetic composition and molecular phenotype. Obstacles to this goal are the absence of an effective means to interpret patient genetic/omic data for clinical use in diverse patient populations. Creating animal models to generate reliable preclinical data for human studies is a fundamental step needed to reach the goal.

In response, the ORIP Division of Comparative Medicine initiated the Pilot Centers for Precision Disease Modeling program to provide advanced animal models to the biomedical community for: 1) examining the causal relationships of genetics and omic information to human biology and disease; 2) validating disease-associated genetic variations and biomarkers; 3) reducing drug candidate attrition; and 4) developing new individualized therapies for monogenic and complex disorders. These Centers are creating pipelines for pre-clinical scientific discovery, disease modeling, and development of interventions based on innovative animal models. Eventually these preclinical pipelines may play an integral role in patient diagnostics, care and therapeutic treatment.

Developing Models of Human Diseases - Explore ways to improve the reproducibility of research using disease models

A Mutant Mouse Centralized Repository for Researchers

June 15, 2017

The Mutant Mouse Resource and Research Center (MMRRC) is a program of the National Institutes of Health (NIH) that strives to expand and ensure access to well-defined, high-quality rodent models for biomedical research. Supported by ORIP’s Division of Comparative Medicine and aligned with ORIP’s 2016‒2020 Strategic Plan to develop novel models of human diseases to study, understand, and eventually cure complex diseases, the MMRRC consists of four centers (at the University of California at Davis, University of Missouri, University of North Carolina at Chapel Hill, and The Jackson Laboratory) that operate as a central repository to accept, cryopreserve, maintain, and distribute mutant mouse strains. By accepting reagents from researchers, the MMRRC promotes an environment of responsible conduct of research, where scientists are obliged to share their resources with each other, which minimizes costs and time associated with the distribution of reagents. From 2010 to April 2017, the MMRRC received more than 8,633 orders from investigators. The MMRRC saves scientists time and costly efforts of having to house, breed, rederive, and characterize mice and conduct duplicative studies due to unexpected phenotypes and experimental variability. The MMRRC now offers next-generation gene sequencing technology of gut microbiota in mice to better equip researchers to conduct reliable and reproducible science, and to avoid unexpected study results. In 2016, the NIH funded the second phase of the newly developed Common Fund’s Knockout Mouse Project (KOMP 2) to make more than 3,000 new genetic knockout mice available through the MMRRC program

Accelerating Research Discoveries by Providing Access to State-of-the-Art Instrumentation - Optimize the instrumentation program through forward-looking program management

Implement Improved metrics to evaluate the S10 Program

March 30, 2017

From the currently submitted applications, ORIP staff drew information about the status of the instruments awarded to the applicant institutions in the last 5 years; that is, fiscal years (FYs) 2011-2015. ORIP’s analysis covered over 80% of all instruments awarded in that period; these instruments are well maintained and being used. Based on the data provided, more clearly defined instructions for responding to questions on instrument status and hours of use were included in funding announcements for FY 2017.

Modify the S10 program requirements and administration to augment its cost effectiveness and utility for the biomedical research community.

In FY 2016, ORIP introduced an opportunity to apply for Special Use Instruments. These instruments can be used in a clinical setting as long as special budgetary and managerial conditions are met to ensure the priority and predominant protected time for biomedical research. One such award was issued for a system consisting of a 3 Tesla MRI scanner and an X-ray angiography interventional system to support research and clinical uses.

Accelerating Research Discoveries by Providing Access to State-of-the-Art Instrumentation - Continue to accelerate research discoveries by providing access to state-of-the-art instrumentation

Stage-specific modulation of antimüllerian hormone (AMH) promotes primate follicular development and oocyte maturation in the matrix-free three-dimensional culture

January 25, 2019

Stage-specific modulation of antimüllerian hormone (AMH) promotes primate follicular development and oocyte maturation in the matrix-free three-dimensional culture Using a rhesus macaque model, investigators cultured primary and secondary follicles in a matrix-free system to determine whether different stages of follicular growth and oocyte maturation would be improved by the addition of AMH. AMH supplementation at the preantral stage and depletion at the antral stage enhanced primate follicular development and oocyte competence in vitro. The improved embryonic development supports in vitro follicle maturation as a potential approach for fertility preservation.

89 Words (Oregon NPRC)

Mucosal T helper 17 (Th17) and T regulatory (Treg) cell homeostasis correlates with acute SIV viremia and responsiveness to antiretroviral therapy (ART) in macaques

January 25, 2019

Researchers investigated the relationship between the mucosal Th17 and Treg cell ratio in response to acute simian immunodeficiency virus (SIV) viremia and combination ART (cART) in rhesus macaques. Th17/Treg ratios decreased during acute SIV infection and were not restored during cART, and this corresponded to increased gut immune activation, markers of microbial translocation, and T-cell exhaustion. A more balanced mucosal Th17/Treg ratio at the time of cART initiation was indicative of a better virologic response to cART and higher peripheral CD4 T cell counts. The results suggest mucosal Th17 and Treg homeostasis influences acute viremia and the response to cART.

124 Words (Washington NPRC)

Identification and functional characterization of a novel Fc gamma-binding glycoprotein in Rhesus Cytomegalovirus (CMV)

January 25, 2019

Investigators used gene mapping and a novel cell-based reporter assay system to characterize a rhesus CMV encoded IgG-Fc gamma (Fcɣ) binding glycoprotein, which acts as a potent antagonist of rhesus FcγR activation. This viral Fcγ receptor is not required to overcome anti-CMV immunity in establishing secondary infections. Future studies of the in vivo consequences of CMV evasion from IgG responses will be explored in nonhuman primate models.

81 Words (Oregon NPRC)

ULTRASONIC AND PHOTOACOUSTIC IMAGING SYSTEM

October 24, 2018

This paper reports improved drug load capacity of nanoparticles and their accumulation in tumors in vivo due to a new fabrication procedure. The ORIP-funded S10OD018505 photo-acoustic instrument and a PET imager were used to assess the therapeutic potential of these newly synthesized nanorods. Research grants from NCI and NIBIB supported the work reported here. Fifteen major users and their scientific collaborators have access to the instrument administered by the Medical Physics Department at the University of Wisconsin Madison.

CONFOCAL LASER-SCANNING MICROSCOPE

October 24, 2018

In this paper, four co-authors report results enabled by the ORIP-funded shared instrumentation award S10OD021806; two separate NIH research awards funded their work. They report that the selective composition of subunits of the glutamate receptor may be responsible for neuronal signaling control. The microscope placed at the BioSpectroscopy Core Research Laboratory at the University of Montana supports work of investigators at the University and regional institutions.

CELL SORTER AND FLOW CYTOMETER

October 24, 2018

Two shared instrumentation awards S10OD020056 and S10RR027050 to Columbia Center for Translational Immunology’s Flow Sorting Services supported research reported in over 60 publications, collectively authored by about hundred investigators. This recent paper states that a combination of allergenic lymphocyte infusion and a treatment to dislodge leukemia cells from the bone marrow decreases the likelihood of cancer relapse compared to the infusion alone.

ORBITRAP ELITE HIGH-RESOLUTION MASS SPECTROMETER

October 24, 2018

The shared instrumentation award S10OD012304 funded a mass spectrometer for the University of Texas MD Anderson Cancer Center’s Proteomics Facility. Over the years, the use of the instrument has supported about 30 different NIH-funded research studies on the molecular identification of human cancers, aiming to improve their diagnosis, treatment, and prognosis. This paper reports that antigen injection combined with the simultaneous extended exposure to silver increases both T cell numbers and their antitumor activity.

Inverted Confocal Microscope

May 1, 2018

As reported in recent three publications, investigators at the University of Delaware use the ORIP-funded confocal microscope (S10OD016361) to study the morphology and activity of cellular organelles in the context of immunity and disease resistance. Another S10-awarded microscope (S10 RR027273) also served these experiments. In work funded by NIGMS grants (R01GM097587, P20GM103446), researchers investigated cellular mechanisms related to the release of immune signals, recognition of pathogens, and generation of defense responses. Using their own, novel, fluorescence-based methods for 3D cellular phenotyping and time-dependent host-pathogen-interactions combined with specialized computation tools for fluorescence imaging data analysis, researchers related organelle dynamics to molecular signaling.

Single Molecule Real Time Sequencer

May 1, 2018

Three articles, published within the last two months, report discoveries enabled by an ORIP-funded sequencer (S10OD018174). The instrument placed in a core facility is used by many scientists; papers cited in these three papaers cumulatively credit 13 different investigators as co-authors, with research grants from six NIH Institutes and Centers. These papers address different scientific topics – genome-wide epigenomic alterations of fetal microglial genes; the integration of metabolite profiling, shotgun sequencing, and exometabolomics to study the structure of microbial communities; impact of formula feeding of premature infants on gut microbiome genes responsible for drug resistance – illustrating the breadth of science enabled by the shared instrument.

750MHZ Wide Bore NMR Spectrometer

May 1, 2018

One strategy in drug design is to inhibit HIV virus replication by targeting the HIV capsid maturation process. This process involves a complex morphological transformation of the HIV Gag protein via an orchestrated series of proteolytic cleavage events. With a 750 MHz NMR spectrometer provided by ORIP’s S10OD12213 grant, critical dynamics of the two HIV capsid peptides (SP1 and CA), in the intermediate assembly state during the capsid maturation, were revealed. Furthermore, it was shown that two maturation inhibitors, Bevirimat and DFH-055, stabilize a helical form of one of the capsid peptides. The spectrometer, shared among 12 major users at U Pittsburgh, contributes to collaborations in this and related research areas across the country.

600 MHz NMR Spectrometer and Time-of-Flight Mass Spectrometer

May 1, 2018

The bacterium Staphylococcus aureus may cause life-threatening hospital-acquired infections. S. aureus uses the sortase A (SrtA) cysteine transpeptidase to display surface protein virulence factors. Researchers at UCLA applied NMR spectroscopy and mass spectrometry to determine the mechanism of SrtA inhibition, using a highly soluble analogue of pyridazinone. Aided by computational chemistry, several compounds with high inhibitor activity were synthesized, suggesting that pyridazinone analogues are promising anti-infective drug candidates. NMR and MS instruments used in the study were supported by the S10OD016336 and S10RR025631 shared instrumentation awards; a total of 64 publications report data collected with these instruments.

High-Performance Compute Cluster for Molecular Science

March 14, 2018

UC Berkeley researchers study metal-mediated organic syntheses with a goal of preparing classes of pharmaceutical intermediates. These two papers report on different catalytic reactions and different functionalization of different bonds (C-H, C-N, C-O and C-S bonds in amines, ethers, sulfides and their derivatives). In both studies, an ORIP-awarded high-performance computer (S10OD023532) augmented chemistry and biophysics experiments to provide a quantitative assessment of reaction rates, reaction pathways, energy barriers, and transition states. Also, computations gave deeper insight into bond-selectivity. The just-installed computer benefits over 20 investigators at the College of Chemistry, supported by grants from several NIH Institutes.

Cryo-EM Microscope and Dedicated Compute Cluster for Single Particle Cryo-EM

March 14, 2018

The ORIP-awarded single-particle cryo-EM (S10OD021741), located at UCSF, was used in experiments to determine the structure of a transient receptor potential melastatin cation channel (TRPM). The member called TRPM4 is impermeable to but activated by calcium, so investigations targeted conformational changes due to calcium binding. The 3A structures resolved with an ORIP-funded computer cluster (S10OD020054) reveal subtle inter-domain interactions, which may be related to the channel’s selectivity and voltage dependence. These two S10 instruments supported work funded by 23 NIH research grants. 

Compute and Data Storage Cluster for Electron Microscopy

March 14, 2018

New cryo-EM detectors allow collecting high-quality data, yielding previously non-attainable high-resolution structures of proteins such as ion channels. Here, researchers at Duke and Scripps report a 4.1 A resolution structure of a member of the transient receptor potential melastatin cation channel family. This result contributes to fundamental understanding of channel activation, gating, and interfacial interactions in the context of cold-sensing. Data were analyzed with an ORIP-awarded computer cluster (S10OD021634). The cluster (awarded in 2016, installed in 2017) made a mark on research supported by NIBIB, NIGMS, and NINDS, and reported in 4 high-profile publications.

High-Performance Compute Cluster and Storage System

March 14, 2018

Researchers at Columbia University report a template-based method for prediction of protein-ligand interactions. In tests, this method compares favorably with existing template-based methods and other computational approaches. Of note is that outcomes suggest the correct identification of off-target drug binding sites and accurate predictions of ligand-protein binding in cases when proteins exhibit a weak sequence similarity to the template. This is one of eleven 2017 papers, cumulatively supported by 20 different NIH-research grants, reporting computational results enabled by the ORIP-awarded compute cluster (S10OD012351) and storage system (S10OD021764).

Structure-based prediction of ligand–protein interactions on a genome-wide scale

February 27, 2018

Researchers at Columbia University report a template-based method for prediction of protein-ligand interactions. In tests, this method compares favorably with existing template-based methods and other computational approaches. Of note is that outcomes suggest the correct identification of off-target drug binding sites and accurate predictions of ligand-protein binding in cases when proteins exhibit a weak sequence similarity to the template. This is one of eleven 2017 papers, cumulatively supported by 20 different NIH-research grants, reporting computational results enabled by the ORIP-awarded compute cluster (S10OD012351) and storage system (S10OD021764).

Targeting Neoplastic Pericytes to Improve Treatment of Brain Tumors

February 22, 2018

A major obstacle for drug delivery to malignant brain tumors is the existence of a Blood Tumor Barrier (BTB).  Scientists at the Cleveland Clinic discovered that glioma stem cell (GSC)-derived pericyte coverage of tumor vasculature is inversely correlated with glioblastoma patient survival after chemotherapy. Using a PerkinElmer IVIS Spectrum CT (S10OD18205), one of 9 small-animal multi-modality CT imagers funded by the ORIP Shared Instrumentation Program in the last 3 years, researchers demonstrated that targeting the GSC-derived pericytes disrupts the BTB, and enhances the chemotherapeutic efficacy. Targeting neoplastic pericytes to significantly improve treatment of brain tumors may hold promise.

Novel Agent for Redox-Activated Photoacoustic Imaging-Guided Photothermal Cancer Therapy

February 22, 2018

Scientists at the University of Wisconsin designed an ultra-small molybdenum-based cluster agent with long in-vivo-circulation half-life for photoacoustic (PA) image-guided photothermal therapy. Accumulating in the tumor, these clusters self-assemble into larger nanoclusters which absorb near-infrared light. Using an ultrasonic and photoacoustic imaging system (S10OD18505) that serves 13 major projects and was funded by the ORIP Shared Instrumentation Program, investigators demonstrated efficacy of these clusters for PA image-guided tumor ablation in-vivo. These findings may establish a new paradigm for PA imaging agents, an approach that bridges the conventional concepts of "molecule" and "nano" in the bioimaging field.

Delineation of Brain Activity at the Columnar Level by fMRI

February 22, 2018

The fMRI blood oxygenation level-dependent (BOLD) signal has specificity to detect brain activity at the columnar level. Using a 9.4T MRI system (S10 RR017799), that is shared among 12 users and was funded by the Shared Instrumentation Grant Program, researchers at Vanderbilt University demonstrated that BOLD signal is aligned spatially with the local field potential signals from multi-channel in-situ electrode array. Such arrays are considered a gold standard to measure brain activity. This work shows that the intrinsic resolution of the brain-activation signal detected by the high-field fMRI BOLD method approaches the spatial precision of invasive multi-electrode electrophysiology.

In-depth Proteomic Survey of the Postnatal Human Brain

February 22, 2018

Researchers at Yale School Medicine quantified regional distribution of over 5000 proteins in gray matter tissue samples of developing human brain. By integrating the protein data with existing whole-transcriptome sequencing from the BrainSpan project, they noted larger regional differences in protein abundance than in RNA abundance. Comparison of structurally similar neocortical regions indicated presence of potential “protein only” region markers. Two ORIP-funded instruments were used in the study: a liquid chromatography system (S10OD019967) and a mass spectrometer (S10OD018034). Over the years, these instruments supported many projects funded by NIGMS, NINDS, NIDDK, NCI, NIAID, NHLBI, NIDA, NIAMS, NEI, and NIA.

Deletion of Nhe1 in Astrocytes is Associated with Reduced Reactive Astrogliosis and Less Ischemic Brain Damage in Mice

February 22, 2018

Researchers at University of Pittsburgh used the ORIP-funded confocal microscope (S10OD021540) in the study of the role of the astrocytic NHE1 protein in development of reactive astrogliosis and neurovascular damage after ischemic stroke. In a mouse model, deletion of astrocytic Nhe1 gene inhibited astrogliosis, reduced stroke volume, prevented blood-brain-barrier damage, and improved regional cerebral blood flow after ischemic stroke, providing evidence of causative role of the NHE1 protein in reactive astrogliosis and neurovascular damage after ischemic injury. The instrument, placed in Center for Biologic Imaging, supports projects in diverse fields such as cell biology, developmental biology, neurobiology, and infectious disease.

Provide Support for Technologies

March 30, 2017

In fiscal year (FY) 2016, the S10 Shared/High-End Instrumentation Program funded 107 awards. As in the past, the Program responded to the needs of researchers from across the nation by funding different types of instruments proportionally to requests received and covering a broad range of technologies; including, X-ray detectors, mass and NMR spectrometers, atomic force, light and electron microscopes, calorimeters, sequencers, biomedical imagers, computers and data storage systems. The Program responds to the emerging needs of the researchers as new technologies become available and enter the market; this year the Program awarded a 3D printer, which is used to create specialized nozzles for X-ray free electron laser imaging of molecular assembly structures.

Collectively, instruments awarded in FY 2016 will immediately benefit the research of almost 2000 investigators supported by grants from all NIH Institutes and Centers, several other Federal agencies including NSF, DOD, DOE, NASA, DARPA, over 80 private foundations, and start-up funds for new faculty at academic institutions.

Partner with NIH ICs

As part of an NIH-wide focus, ORIP is interested in best practices for data generation, management and sharing. ORIP, NIGMSNLM, and BD2K, collaborated to issue the notice (NOT-OD-16-091) requesting information on Data Annotation in Biomedical Core Research Facilities and Related Needs for Community Education and Training. (See the Executive Summary of results).