ORIP Strategic Plan 2021–2025 Archive

 

 


Progress on Theme 1: Animal Models to Advance the Study of Human Disease

Programs and Activities Highlights

  • INCLUDE (INvestigation of Co-occurring conditions across the Lifespan to Understand Down syndromE) Project 
    ORIP is participating in INCLUDE, the NIH-wide initiative on Down syndrome research. In collaboration with other NIH Institutes, Offices, and Centers, ORIP signed on to the reissue of RFA-OD-20-005, titled, “Transformative Research Award for the INCLUDE Project (R01 Clinical Trial Not Allowed).”

  • Nonhuman Primate Developmental Genotype-Tissue Expression (NHP dGTEx) Research Center 
    ORIP is co-funding a National Human Genome Research Institute–managed dGTEx program, HG21-026, titled, “NHP dGTEx Project (U24 Clinical Trials Not Allowed).” The purpose of this funding opportunity is to solicit applications for the NHP dGTEx Research Center. The Center will perform four major functions: (1) create a tissue resource of multiple reference tissues across developmental stages in NHPs, (2) perform transcriptome sequencing and other genomic analysis of single-cell and bulk tissues, (3) analyze gene expression patterns in NHPs and compare them to human gene expression patterns, and (4) make the tissue samples and data available and usable for the research community.

  • Grassroots Efforts to End Structural Racism Throughout the U.S. National Institutes of Health
    An open letter by NIH staff to the Director of the NIH helped to catalyze the NIH UNITE Initiative for Ending Structural Racism. ORIP staff participated in these grassroots efforts, as well as in the UNITE Initiative, to lead change within the NIH and the biomedical research ecosystem.

  • Severe Combined Immunodeficient Pig Models
    ORIP supports development of immunodeficient swine research models and resources to enable biomedical research on a wide range of human diseases. Two ORIP staff members served as panelists at the January 2022 virtual meeting, “Severe Combined Immunodeficient (SCID) Pig Models: Industry and Academia’s Needs.” The panel discussed the need for novel SCID pig models in various fields, such as stem cell therapy, regenerative medicine, cancer therapeutics, and organ transplantation. In addition to funding the National Swine Resource and Research Center, ORIP is supporting two projects focusing on improvement of SCID pigs with natural mutation or creating new mutants using state-of-the-art technologies.

  • ORIP 2021–2022 Resource and Research Centers
    ORIP supports 97 resource and research centers that develop animal models of human biology and disease. These centers develop, characterize, house, cryopreserve, and distribute both wild-type reference strains of animals, as well as mutant and genetically modified strains.
  • ORIP’s Rapid Response to the COVID-19 Pandemic
    ORIP issued administrative supplements to many of its research resource centers in 2021 to support the development of new animal models and other resources specifically designed to facilitate research on SARS-CoV-2 or to support research projects related to COVID-19.
  • ORIP Workshop: Validation of Animal Models and Tools for Biomedical Research
    ORIP—in collaboration with the National Heart, Lung, and Blood Institute; National Institute of Diabetes and Digestive and Kidney Diseases; National Institute of General Medical Sciences; National Institute of Neurological Disorders and Stroke; and National Institute on Aging—held a series of virtual workshops between November 2020 and January 2021 to discuss the status and needs regarding the validation and rigor/reproducibility of animal models used in biomedical research.
  • ORIP Encourages the Development of Resources and Technologies for Enhancing Rigor, Reproducibility, and Translatability of Animal Models in Biomedical Research
    ORIP has issued a Notice of Special Interest (NOT-OD-22-039) for 2-year projects to support exploratory/developmental and highly innovative projects aimed at developing broadly applicable technologies, tools, and resources for validating animal models and enhancing the rigor, reproducibility, and translatability of animal research.

ORIP-Supported Research Highlights

  • A Basement Membrane Discovery Pipeline Uncovers Network Complexity, Regulators, and Human Disease Associations
    Basement membranes are sheet-like networks of extracellular matrix proteins that support and surround tissues. Defects in these membranes are associated with such human conditions as diabetes, kidney disorders, cancer, and cardiovascular issues. Researchers developed an experimental pipeline to unravel the full scale of proteins that make up basement membranes by combining large-scale data analysis, genetic studies, and imaging to track basement membranes in living animals. The study led to the identification of more than 200 human basement membrane proteins and new genetic disease associations, which could lead to better diagnosis and treatment of basement membrane defects in cardiovascular and kidney disorders, fibrosis, and aging.

  • Voltage Imaging Identifies Spinal Circuits That Modulate Locomotor Adaptation in Zebrafish
    Spinal circuits underlying rhythmic locomotion are well described; however, little is known about how the network modulates its output strength, in part due to the difficulty of recording spinal neurons during behavior. The authors used voltage imaging to map the membrane potential of large populations of glutamatergic (V3) neurons throughout the spinal cord of the larval zebrafish during fictive swimming. Optogenetic activation of V3 neurons led to stronger swimming and longer bouts without affecting tail beat frequency. Genetic ablation of V3 neurons led to reduced locomotor adaptation. Based on these findings, V3 neurons appear to be a critical driver of locomotor adaptation in zebrafish.

  • A Simple Standard for Sharing Ontological Mappings (SSSOM)
    Diseases can be represented by identifiers in diverse databases. Merging these databases without accurate mappings, however, might result in loss of important information, resulting in inaccurate or incorrect disease diagnoses. The SSSOM addresses shortcomings in current bioinformatics information mapping schemas. SSSOM is a simple, standardized format that facilitates the sharing of high-quality mappings between different data sources, bringing together biomedical databases and enabling more accurate diagnosis of diseases. In this report, the authors present the SSSOM standard, describe several use cases, and survey current work in this area.

  • Ceramides Are Early Responders in Metabolic Syndrome Development in Rhesus Monkeys
    Metabolic syndrome negatively affects millions of people in the United States. Researchers investigated 16 overweight male rhesus macaques, half of which spontaneously developed metabolic syndrome. Circulating sphingolipids were altered early in the development of insulin resistance, independent of changes in adiposity and before loss of euglycemia. The interactions among circulating sphingolipids and among other insulin-responsive biomolecules—apparent in healthy animals—were lost in the impaired monkeys before the onset of insulin resistance. Thus, lipid profiling can be used to identify early biomarkers of insulin resistance and shed light on the underlying biology of metabolic impairment.

  • Antithetic Effect of Interferon-α on Cell-Free and Cell-to-Cell HIV-1 Infection
    HIV-1 experiences a strong bottleneck during transmission; viruses with higher resistance to host innate immunity tend to be transmitted. Researchers investigated resistance to interferon-alpha (IFN-α)–mediated antiviral effects in HIV-1 isolated at the transmission/founder (TF) and chronic control (CC) phases of infection. IFN-α suppresses cell-to-cell transmission of CC virus but only weakly affects the TF virus. The researchers found that IFN-α enhances cell-free HIV-1 infection, particularly that of CC virus, in a virus-cell density-dependent manner. These results provide insights into how HIV-1 evolves to counteract or hijack host immunity.

  • Neuropathology and Virus in Brain of SARS-CoV-2-Infected Non-human Primates
    Investigators observed neuroinflammation, microhemorrhages, brain hypoxia, and neuropathology that are consistent with hypoxic-ischemic injury in SARS-CoV-2-infected nonhuman primates (NHPs). This effect is seen among infected animals that do not develop severe respiratory disease, which may provide insight into neurological symptoms associated with long COVID-19. Sparse virus was detected in brain endothelial cells but did not associate with the severity of central nervous system injury. These results are indicative of neuropathogenesis of SARS-CoV-2 infection and demonstrate SARS-CoV-2-infected NHPs are a relevant animal model for investigating COVID-19 neuropathogenesis. Read more here.
  • Reduced Infant Rhesus Macaque Growth Rates Due to Environmental Enteric Dysfunction and Association with Histopathology in the Large Intestine 
    Researchers characterized environmental enteric (relating to the intestines) dysfunction (EED) among infant rhesus macaques (n=80, both sexes) naturally exposed to enteric pathogens commonly linked to human growth stunting. Despite atrophy and abnormalities observed in the small intestine, poor growth trajectories and low serum tryptophan (an amino acid needed for protein and enzymes) levels were correlated with increased histopathology (microscopic tissue examination for disease manifestation) in the large intestine. This study provides insight into the mechanisms underlying EED and indicates that the large intestine may be an important target for therapeutic intervention.

  • Complex Decay Dynamics of HIV Virions, Intact and Defective Proviruses, and 2LTR Circles Following Initiation of Antiretroviral Therapy 
    In people living with HIV-1 who start antiretroviral therapy, virus in blood decreases rapidly to below detection, but remaining infected cells may become part of the latent reservoir. Researchers investigated viral decay dynamics and identified decay processes with pronounced differences between intact and defective proviruses. Infected cells that survive second-phase decay may down-regulate HIV-1 gene expression and enter the stable latent reservoir. This research provides insight into meaningful latent reservoir markers and mechanisms for elimination of cells with intact viral genomes.

  • Phagocytosis by an HIV Antibody Is Associated with Reduced Viremia Irrespective of Enhanced Complement Lysis 
    Researchers used the broadly neutralizing antibody (bNAb)10E8v4 targeting the HIV Env protein to examine the role of antibody-mediated effector and complement (C’) activity when 10E8v4 was administered prophylactically to rhesus monkeys challenged with simian–human immunodeficiency virus (SHIV). With sub-protective dosing, the researchers found a 78–88% reduction in post-acute viremia that was associated with 10E8v4-mediated phagocytosis. These results suggest that effector functions inherent to unmodified 10E8v4 contribute to therapeutic efficacy against SHIV, while C’ functions do not contribute to efficacy in this context. This research informs the design of bNAb modifications for improving the protective efficacy of this therapeutic approach against HIV.

  • Functional and Ultrastructural Analysis of Reafferent Mechanosensation in Larval Zebrafish 
    All animals need to differentiate between exafferent stimuli (caused by the environment) and reafferent stimuli (caused by their own movement). Researchers characterized how hair cells in zebrafish larvae discriminate between reafferent and exafferent signals. Dye labeling of the lateral line nerve and functional imaging was combined with ultra-structural electron microscopy circuit reconstruction to show that cholinergic signals originating from the hindbrain transmit efference copies and dopaminergic signals from the hypothalamus may affect threshold modulation. Findings suggest that this circuit is the core implementation of mechanosensory reafferent suppression in these young animals.

  • Genetic Control of the Pluripotency Epigenome Determines Differentiation Bias in Mouse Embryonic Stem Cells
    Embryonic stem cells (ESCs) show an unlimited capacity for self-renewal and the ability to become any cell type in the body. Yet mechanisms for variation of ESCs from genetically diverse individuals remain largely unknown. Investigators studied regulation of cell state transitions in mouse ESCs derived from genetically diverse mouse strains and found differences in developmental potential of mouse ESCs in vitro. Recent experiments have shown that differences in cell-fate choice during development may be critical in predisposing individuals to complex diseases due to underlying differences in cell-type composition.
  • Blastocyst Development after Fertilization with In Vitro Spermatids Derived from Nonhuman Primate Embryonic Stem Cells
    Researchers investigated whether functional spermatids (immature forms of sperm cells) can be derived in vitro from nonhuman primate pluripotent stem cells. Rhesus macaque pluripotent stem cells were differentiated into spermatogenic germ cell linages and matured in vitro to form spermatids that were capable of fertilizing oocytes (female or germ cells involved in reproduction) by injection. Successful in vitro preimplantation embryo development was observed in approximately 12% of zygotes. The data suggest potential mechanisms to address male infertility.
  • Natural Disaster and Immunological Aging in a Nonhuman Primate
    Survivors of weather-related disasters exhibit early onset of age-related diseases. Investigators examined the impact of Hurricane Maria and its aftermath on immune cell gene expression in age-matched, cross-sectional samples from free-ranging rhesus macaques living on an isolated island. Living through an intense hurricane and its aftermath was associated with expression of key immune genes, dysregulated protein regulation networks, and greater expression of inflammatory immune cell–specific marker genes. These findings illuminate how natural disasters might become biologically embedded and contribute to earlier onset of disease and death.
  • New Resources for the Drosophila 4th Chromosome: FRT101F Enabled Mitotic Clones and Bloom syndrome helicase Enabled Meiotic Recombination
    Seventy percent of the genes on the 4th chromosome of Drosophila melanogaster have human homologs that have a disease association. Yet, this chromosome is difficult to study because it lacks mitotic and meiotic recombination. Investigators developed technologies and stocks as a resource for the community, which enable genetic analysis of mutations on the 4th chromosome.
  • The Pigtail Macaque (Macaca nemestrina) Model of COVID-19 Reproduces Diverse Clinical Outcomes and Reveals New and Complex Signatures of Disease
    Animal models that reproduce clinical outcomes of human COVID-19 disease are critical for understanding SARS-CoV-2 viral and immune dynamics. Investigators demonstrate that pigtail macaques recapitulate important features of COVID-19 and reveal new immune and viral dynamics of SARS-CoV-2 infection.
  • Precise Visuomotor Transformations Underlying Collective Behavior in Larval Zebrafish
    Brain mechanisms involved in collective social behavior are mostly unknown. Investigators found how zebrafish transform visual cues into fast and accurate movement decisions when swimming in schools. For example, a fish might use the height of the fish surrounding it to estimate the distance to its neighbors.
  • Multiview Confocal Super-Resolution Microscopy
    Researchers, including NIH scientists, report major improvements in confocal microscopy, a “workhorse” biomedical imaging technology. By harnessing new multiview light sensing optical methods in combination with deep-learning image reconstruction, researchers have improved the spatial and temporal resolutions, speed, and depth penetration of confocal microscopy and were able to acquire high-resolution images with less light. Researchers demonstrated their improved capabilities on fixed and live samples of single cells, fly wings, and mouse heart and brain tissue.
  • AAV Capsid Variants with Brain-Wide Transgene Expression and Decreased Liver Targeting After Intravenous Delivery in Mouse and Marmoset
    Gene therapy using the shell (capsid) of adeno-associated viruses (AAVs) is increasingly being explored as a therapeutic option for debilitating disorders of the central nervous system. Investigators achieved organ-specific targeting of adeno-associated virus capsids after intravenous delivery in mice and marmosets. These results constitute an important step forward toward achieving the goal of engineered adeno-associated viruses that can be used to broadly deliver gene therapies to the central nervous system in humans.
  • BNT162b Vaccines Protect Rhesus Macaques from SARS-CoV-2
    The preclinical development of two BNT162b vaccine candidates against SARS-CoV-2 was performed in rhesus macaques at the Southwest National Primate Research Center.
  • In Vitro and In Vivo Functions of SARS-CoV-2 Infection-Enhancing and Neutralizing Antibodies
    Researchers isolated neutralizing antibodies against the receptor-binding domain (RBD) or N-terminal domain (NTD) of SARS-CoV-2 spike from COVID-19 patients. RBD and NTD antibodies mediated both neutralization and infection enhancement in vitro. RBD-neutralizing antibodies having cross-reactivity against coronaviruses protected against SARS-CoV-2 in vivo.
  • A Novel Tau-Based Rhesus Monkey Model of Alzheimer’s Pathogenesis
    Researchers developed a new rhesus monkey model of Alzheimer’s disease by targeting the entorhinal cortex with an adeno-associated virus expressing a double tau mutation.
  • Cryopreservation Method for Drosophila melanogaster Embryos
    Researchers reported a robust and efficient method for cryopreservation of Drosophila melanogaster embryos. The optimized method resulted in >10% of embryos developing into fertile adults after cryopreservation for 25 distinct strains from different sources.

Progress on Theme 2: Innovative Instruments and Equipment to Accelerate Research Discoveries

Programs and Activities Highlights

  • ORIP Research Instrumentation Awards (S10)
    ORIP S10 shared instrumentation programs awarded 128 scientific instruments to 84 domestic research institutions among 32 states and territories in 2021. Instrument types included biomedical imagers, cell analyzers, high-performance computers, electron microscopes, mass spectrometers, optical microscopes, magnetic resonance spectrometers, radiological/surgical instruments, and sequencers.
  • ORIP Support of the IDeA Program
    ORIP partnered with the National Institute for General Medical Sciences to co-fund 11 S10 research instrument awards to academic and nonprofit research institutions in 8 Institutional Development Award (IDeA)–eligible states in 2021. The types of instruments awarded included cell analyzers, high-performance computers, electron microscopes, mass spectrometers, optical microscopes, and sequencers.
  • New Funding Opportunity for Institutions to Modernize the Functions and Operations of Existing Research Facilities
    ORIP invited qualified academic or research institutions to apply for support to purchase and install advanced equipment to enhance and modernize research-supporting operations of biomedical research facilities (PAR-21-326). Core facilities, animal research facilities, and other similar shared-use facilities at academic and nonprofit research institutions will be supported by this program.
  • Virtual Construction and Renovation Site Visits for Awarded C06/G20 projects
    ORIP performed more than 70 final site visits virtually in 2021 covering more than 90 construction/renovation projects that are near the end of 10- or 20-year federal oversight periods. Information on overall impact, usage, and maintenance of grant-supported spaces is being reviewed. Most of these grant-supported spaces continue to be used for the biomedical research proposed in their original applications.

Research Highlights from Investigators Utilizing ORIP-Supported Instrumentation

  • Toxic SOD1 Trimers Are Off-Pathway in the Formation of Amyloid-Like Fibrils in ALS
    The aggregation of proteins into large insoluble species is a hallmark of many neurodegenerative diseases, but recent evidence suggests that smaller soluble aggregates—such as nonnative superoxide dismutase (SOD1) trimeric oligomers—are responsible for neuronal death. Both factors must be considered in the development of therapeutics for neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS). Investigators stabilized the trimeric form of SOD1, which decreased the formation of larger aggregates while increasing toxicity to cells. They showed that that trimeric SOD1 is off-pathway in the formation of protective SOD1 inclusion bodies. These results provide insight into the design of therapeutic interventions for ALS.

  • Basis of Narrow-Spectrum Activity of Fidaxomicin on Clostridioides difficile
    Fidaxomicin, an RNA polymerase inhibitor, is used to treat Clostridioides difficile infection. The molecular basis of the pathogen’s narrow-spectrum activity in the gut microbiome, however, is unknown. Investigators used cryogenic electron microscopy to determine the structure of C. difficile RNA polymerase in complex with fidaxomicin. They identified a crucial fidaxomicin-binding determinant of the RNA polymerase that is absent in most gut microbiota. Structural, biochemical, genetic, and bioinformatic analyses were used to identify the sensitizing element for fidaxomicin’s narrow-spectrum activity. These findings can be applied toward a targeted C. difficile drug design.

  • A Naturally Inspired Antibiotic to Target Multidrug-Resistant Pathogens
    Antibiotic resistance has contributed to an increasing number of deaths associated with gram-negative bacterial infections. Colistin, a naturally derived antibiotic, is used as a last-resort treatment; however, the recent spread of mobilized colistin-resistance gene (mcr-1) might lessen colistin’s usefulness. Researchers proposed that a solution to mcr-1-mediated resistance might have evolved among naturally occurring colistin congeners. They conducted a bioinformatic analysis and identified a biosynthetic gene cluster that is predicted to encode a structurally divergent colistin congener. The researchers synthesized macolacin using this structure and provided evidence for its utility in a mouse neutropenic infection model.

  • Omicron Spike Function and Neutralizing Activity Elicited by a Comprehensive Panel of Vaccines

    The SARS-CoV-2 Omicron variant comprises several sublineages, including BA.1, BA.2, BA.3, BA.4, and BA.5. Several of these sublineages differ in the sequence of the spike glycoprotein, which interacts with the receptor angiotensin-converting enzyme 2 (ACE2). The investigators aimed to understand how the different spike mutations in the Omicron variant sublineages affect host receptor engagement and membrane fusion. They showed that the mutations affect ACE2 binding, fusogenicity, and plasma-neutralizing activity in response to infection or clinical vaccines. These data indicate the effectiveness of vaccine boosters in conferring protection against Omicron-induced severe disease.

  • A Molecular Analysis of Memory B Cell and Antibody Responses Against Plasmodium falciparum Merozoite Surface Protein 1 in Children and Adults from Uganda
    Novel interventions for malaria, including an efficacious vaccine, are critically needed to reduce the incidence of disease. In this study, researchers sought to understand how memory B cell and antibody responses develop over the course of lifelong Plasmodium falciparum exposure. They demonstrated the evolution of full-length P. falciparum merozoite surface protein 1 (PfMSP1)–specific humoral immune response with cumulative pathogen exposure. They reported a shift from IgM+ to IgG+ B cell memory, diversification of B cells from germline, and stronger recognition of PfMSP1 variants by the plasma IgG repertoire. These results help elucidate the development of B-cell responses to P. falciparum infection.

  • Dual-Function Antibody Conjugates for Multimodal Imaging and Photoimmunotherapy of Cancer Cells
    Precision imaging is an important tool in cancer diagnostics and guiding therapies. The investigators proposed a dual-function antibody conjugate (DFAC) comprising an FDA-approved photosensitizer and a naphthalocyanine-based photoacoustic dye for multimodal infrared imaging and demonstrated the utilization of DFACs for multimodal imaging and photodynamic treatment of squamous cell carcinoma cell line. The proposed DFACs—which were generated by complementing fluorescence imaging with photoacoustic imaging—have potential use in precision imaging applications for preclinical and clinical translation, such as guiding tumor resection surgeries and photodynamic treatment of residual microscopic disease, thereby minimizing local recurrence

  • Structure-Based Design and Antigenic Validation of Respiratory Syncytial Virus G Immunogens
    Respiratory syncytial virus (RSV) is a leading cause of severe lower respiratory tract disease of children, the elderly, and immunocompromised individuals. The investigators demonstrated the use of an RSV glycoprotein (G) variant, S177Q protein, to develop RSV vaccines. The RSV G S177Q protein retains high-affinity binding to protective human and mouse monoclonal antibodies and has equal reactivity as wild-type RSV G protein to human reference immunoglobulin to RSV. Additionally, they determined the high-resolution crystal structure of RSV G S177Q protein in complex with the anti-RSV G antibody 3G12, further validating its antigenic structure. These studies suggest that an engineered RSV G protein is an immunogen candidate for developing RSV vaccines

  • Proteomic Analysis of Microtubule Inner Proteins (MIPs) in Rib72 Null Tetrahymena Cells Reveals Functional MIPs 
    Microtubules are dynamic protein structures within cells that perform diverse essential functions, including providing the force required to bend cilia (hairlike structures on the outside of cells) to allow cells to move through fluid. Researchers studied the structure and function of microtubule inner protein Fap115 in the motile cilia to better understand ciliary structure and function. Using mass spectrometry, proteomic analysis, and cryo-electron tomography, the region of microtubules where Fap115 proteins localize was identified. Using a genetic knockout of Fap115 in Tetrahymena thermophila, a unicellular eukaryote, researchers revealed that loss of Fap115 function resulted in aberrant ciliary motion and disrupted cell swimming.

  • Mechanism of Integrin Activation by Talin and Its Cooperation with Kindlin 
    Talin is a cytoskeletal protein with many cellular functions. However, how talin head terminal (talin-H) operates in the context of full-length talin and its surroundings remains unknown. Investigators showed that while being capable of inducing integrin activation, talin-H alone exhibits unexpectedly low potency versus a constitutively activated full-length talin. They found that the large C‑terminal rod domain of talin (talin-R), which otherwise masks the integrin binding site on talin-H in inactive talin, dramatically enhances the talin-H potency by dimerizing activated talin and bridging it to the integrin co-activator kindlin-2. These data provide crucial insight into the mechanism of talin and its cooperation with kindlin to promote potent integrin activation, cell adhesion, and signaling

  • Integrated Analysis of Plasma and Single Immune Cells Uncovers Metabolic Changes in Individuals with COVID-19
    A better understanding of the metabolic alterations in immune cells during infection by SARS-CoV-2 infection may elucidate the wide diversity of clinical symptoms experienced by individuals with COVID-19. Investigators reported metabolic changes associated with the peripheral immune response of individuals with COVID-19. The results revealed a robust interplay between plasma metabolites and cell type–specific metabolic reprogramming networks that were associated with disease severity and could predict survival.

  • IMPDH1 Retinal Variants Control Filament Architecture to Tune Allosteric Regulation
    Purines are essential components of RNA and DNA and play roles in metabolism. Investigators studied a regulatory factor for making purines: inosine-5′-monophosphate dehydrogenase 1 (IMPDH1), which plays a unique role in retinal metabolism. Mutation of IMPDH1 causes human blindness. Investigators showed that canonical human IMPDH1 assembles into filaments with different structures depending on its activity state. These results provide insight into regulatory mechanisms for IMPDH1.

  • Immune Correlates Analysis of the mRNA-1273 COVID-19 Vaccine Efficacy Clinical Trial
    Investigators determined that antibodies are the correlate of protection in vaccinated individuals enrolled in the Moderna coronavirus efficacy (COVE) Phase 3 clinical trial. Vaccine recipients were assessed for neutralizing and binding antibodies as correlates of risk for COVID-19 disease and as correlates of protection. All markers were inversely associated with COVID-19 risk and directly associated with vaccine efficacy. These results help define immune marker correlates of protection and may guide approval decisions for messenger RNA (mRNA) and other COVID-19 vaccines.

  • Selective G Protein Signaling Driven by Substance P–Neurokinin Receptor Dynamics
    Investigators determined the cryogenic-electron microscopy structures of active neurokinin-1 receptor, a G protein–coupled receptor, bound to neuropeptide substance P (SP) or the G protein q-biased peptide SP6–11. This data unveils the molecular mechanism of how two stimuli (SP and neurokinin A) yield distinct G protein signaling at the same G protein–coupled receptor.

  • Spatial Transcriptomics Using Combinatorial Fluorescence Spectral and Lifetime Encoding, Imaging, and Analysis
    Investigators introduced a spatialomics technology—termed Multi Omic Single-scan Assay with Integrated Combinatorial Analysis (MOSAICA)—that integrated in situ labeling of mRNA and protein markers with combinatorial fluorescence spectral and lifetime encoded probes, spectral and time-resolved fluorescence imaging, and machine learning–based decoding. Investigators demonstrated MOSAICA’s multiplexing scalability, applied this technology for multiplexed analysis, and showed simultaneous co-detection of protein and mRNA in multiple cell and tissue types.

  • Severely Ill COVID-19 Patients Display Impaired Exhaustion Features in SARS-CoV-2–Reactive CD8+ T Cells 
    Investigators studied single-cell transcriptomes of >80,000 virus-reactive CD8+ T cells from COVID-19 patients using a modified antigen-reactive T cell enrichment (ARTE) assay and found substantial diversity in the nature of CD8+ T cell responses to SARS-CoV-2 infection among patients.
  • Imbalance of Regulatory and Cytotoxic SARS-CoV-2–Reactive CD4+ T Cells in COVID-19
    Researchers reported a study of CD4+ T cells in the immune responses of hospitalized and non-hospitalized patients with SARS-CoV-2 infection and identified distinct gene expression patterns of SARS-CoV-2–reactive CD4+ T cells associated with disease severity.
  • A Noncoding RNA Modulator Potentiates Phenylalanine Metabolism in Mice
    Investigators demonstrated that the mouse long noncoding RNA (lncRNA) Pair and human lncRNA HULC associate with phenylalanine hydroxylase and can be utilized to develop mouse and human induced pluripotent stem cell (iPSC) models of phenylketonuria for preclinical research.
  • An NR2F1-Specific Agonist Suppresses Metastasis by Inducing Cancer Cell Dormancy
    Investigators discovered an agonist of the nuclear receptor NR2F1 that activates dormancy programs in malignant cells. This dormancy program arrested the growth of multiple human cell lines and patient-derived organoids and inhibited lung metastases of head and neck squamous cell carcinomas in mice.

Progress on Theme 3: Specialized Research Training in Animal Models and Related Resources

Programs and Activities Highlights

  • ORIP Supports Individual Predoctoral Fellowships to Promote Diversity in Health-Related Research
    ORIP accepts applications from highly qualified veterinary students or holders of degrees in veterinary medicine to enhance the diversity of the health-related research workforce (PA-21-052).

  • ORIP Provides Support for Early-Stage Investigators Using Nonhuman Primate Research Models
    This funding opportunity announcement (PAR-20-258) provides early-stage investigators with support and “protected time” (up to 5 years) for intensive, research-focused career development program activities under the guidance of an experienced mentorship team with expertise in both the preclinical application of nonhuman primate models and in translation of the results from such studies to clinical application. Participating NIH Institutes/Centers/Offices (ICOs) include the National Institute of Allergy and Infectious Diseases (lead ICO), National Institute on Aging, National Institute on Alcohol Abuse and Alcoholism, National Center for Complementary and Integrative Health, and ORIP.

ORIP-Supported Research Highlights

  • Characterizing the Metabolic Role of STAT3 in Canine Osteosarcoma
    Canine osteosarcoma represents an ongoing therapeutic challenge, and researchers are interested in targeting aberrant signaling pathways associated with the disease. Constitutive activation of STAT3—a transcription factor that mediates numerous biological processes—contributes to survival and proliferation of osteosarcoma cell lines. Investigators characterized metabolic benchmarks associated with STAT3 loss in canine osteosarcoma. Deletion of STAT3 was associated with decreased basal and compensatory glycolysis and diminished invasive capacity. These data support the contribution of STAT3 to aerobic glycolysis and cellular invasive capacity in canine osteosarcoma. Further work is needed to leverage STAT3 as a therapeutic target.

  • Pharmacogenetic Gene–Drug Associations in Pediatric Burn and Surgery Patients
    Simultaneous administration of many medications is common in management of critically ill patients. The researchers investigated drug–drug interactions in these treatments during hospitalization, which might decrease drug efficacy or increase adverse reactions. Genetic and medication data from 30 pediatric burn and surgery patients were analyzed to identify pharmacogene–drug associations. Nineteen patients were identified with predicted altered gene functions. Approximately one-third of the patients tested had functionally impactful genotypes in each of the primary drug metabolizing pathways. This study suggests that the vast variability in drug efficacy is partly due to genetic variants and that pharmacogenetic analysis may help optimize dosing regimens

  • Structural Basis for Ultrapotent Antibody-Mediated Neutralization of Human Metapneumovirus
    No vaccines or therapeutics currently are available for human metapneumovirus (hMPV), a leading cause of morbidity and hospitalization among children worldwide. For vaccine development, the investigators isolated a panel of human monoclonal antibodies (mAbs) against the hMPV fusion (F) protein, the latter of which is the sole target of neutralizing antibodies. They found the majority of the mAbs target diverse epitopes on the hMPV F protein and identified a highly potent mAb, MPV467. They determined the structure of MPV467 in complex with the hMPV F protein, which revealed a complex novel prefusion-specific epitope. These findings revealed the immunodominant antigenic epitopes on the hMPV F protein, identified a mAb therapy for hMPV F disease prevention and treatment, and discovered a prefusion-specific epitope on the hMPV F protein

  • Losartan Blocks Osteosarcoma-Elicited Monocyte Recruitment and, Combined with the Kinase Inhibitor Toceranib, Exerts Significant Clinical Benefit in Canine Metastatic Osteosarcoma
    Osteosarcoma is the most common primary malignant tumor of bone. Overall survival rates for osteosarcoma patients have remained unchanged since improvements associated with the introduction of multidrug chemotherapy protocols in the 1980s. An investigator—under a career development award and training grant, both provided by ORIP—found that a novel therapeutic approach combining losartan and tocerabib was effective in dogs with spontaneous osteosarcoma. This outcome supports further study of this drug combination as a novel therapeutic approach for high-risk patients with metastatic osteosarcoma.

  • Antibody-Based CCR5 Blockade Protects Macaques from Mucosal SHIV Transmission 
    Researchers found that competitive inhibition of HIV Env-CCR5 binding via the CCR5-specific antibody Leronlimab protects male and female rhesus macaques against infection following repeated intrarectal challenges with a CCR5-tropic simian-human immunodeficiency virus (SHIV), suggesting that CCR5 blockade with Leronlimab is a promising approach to HIV prophylaxis.
  • Effects of Persistent Modulation of Intestinal Microbiota on SIV/HIV Vaccination in Rhesus Macaques 
    Researchers evaluated whether probiotics could improve the immunogenicity and protective efficacy of a simian immunodeficiency virus (SIV)/HIV DNA vaccine plus HIV protein vaccine combination in male rhesus macaques and found that a combination of probiotics and vaccination did not affect rectal SIV/HIV target populations or reduce the rate of heterologous SHIV acquisition during intrarectal challenge.
  • Psychosocial Stress Alters the Immune Response and Results in Higher Viral Load During Acute SIV Infection in a Pigtailed Macaque Model of HIV
    Researchers compared commonly measured parameters of HIV progression between singly and socially housed SIV-infected male pigtailed macaques and found that singly housed animals had a higher viral load in the plasma and cerebrospinal fluid and showed greater CD4+ T cell declines than socially housed macaques. These findings suggest that psychosocial stress could augment the progression of HIV infection.


Progress on Theme 4: Awareness of ORIP Resources and Programs

Programs and Activities Highlights

  • Aquatic Models of Human Diseases Special Webinar: Emerging Aquatic Models and Husbandry
    Aquatic animal species, such as zebrafish (Danio rerio), are powerful models for studying human development, behavior, genetics, and disease. Studies indicate that the length, weight, sexual maturation, fecundity, and mortality of zebrafish can vary significantly with different diets, which varies between different facilities and laboratories. The needs and challenges of developing defined diets and optimized feed management strategies for relevant aquatic species used in research were assessed and discussed in the 2018 workshop, “Defined Reference Diets for Zebrafish and Other Aquatic Biomedical Research Models: Needs and Challenges,” convened by ORIP. Because of the workshop, Administrative Supplements for pilot projects of a multiplatform candidate reference diet test for biomedical fish models were awarded to three research resources programs. A summary of the results of those pilots were discussed during the February 2022 webinar, “Aquatic Models of Human Diseases Special Webinar: Emerging Aquatic Models and Husbandry.”
  • Thirteenth Comparative Medicine Resource Directors Meeting: Innovating, Adapting, and Sustaining Resources for a Dynamic Biomedical Landscape
    This virtual meeting held in August 2021 provided a forum for exchange of new information, advances, and ideas and facilitated the development of synergistic working groups, interactions, and collaborations among resources. Session topics included services and research activities, dissemination of specialized knowledge, standard operating procedures, and best practices and support for community outreach.
  • Pre-Application Webinar for the Research Resource Equipment Program
    ORIP held a pre-application webinar for the funding opportunity announcement to support Modern Equipment for Shared-Use Biomedical Research Facilities (PAR-21-326). ORIP staff members assisted potential applicants by explaining the objectives, criteria, and requirements of this funding opportunity announcement. Pre-webinar and live questions from attendees were addressed and answered by program staff.
  • ORIP Webinar: “What Do Veterinarians (Who Are Also Scientists) Bring to Biomedical Research?”
    ORIP's Division of Comparative Medicine supports up to two webinars per year on topics of interest to K01 and F30 awardees. At the fall 2021 meeting, two veterinary scientists discussed their experiences as veterinarians working in biomedical research, as well as the knowledge, skills, and abilities that veterinary scientists bring to the biomedical research enterprise.
  • 2021 National Small Busines Innovation Research (SBIR) Week—Virtual Event
    ORIP participated in this national conference by meeting one-on-one with members of the small business community to provide feedback on project concepts, describe the interest areas of ORIP's Small Business Program, and respond to questions about the SBIR/Small Business Technology Transfer (STTR) application process.

Collaborations with Other NIH Institutes/Centers/Offices

None at this time.

 

Last updated: 11-29-2022