Updates and Current Research from ORIP Grantees


National Primate Research Centers and Other Primate Resources
Parent Grant Number: P51OD011132 PI: Lewin, Jonathan S Title of Parent Project: Support of Yerkes National Primate Research Center Title of Administrative Supplement 1: Developing an NHP model for understanding the biological causes of long COVID-19 pathogenesis Summary of the Supplement 1 The main goal of this project is to establish a rhesus macaque animal model for studying post-acute sequelae of COVID-19. The PI will establish biosafety guidelines and procedures for post-acute sequelae studies in rhesus macaques and will characterize neurological and behavioral findings, which will allow the transfer of convalescent rhesus macaques from ABSL-3 to ABSL-2 facilities. The team will also elucidate the underlying biological causes of post-acute sequelae by performing a battery of molecular, cellular, immune, and physiological assays for pulmonary and cardiovascular functions, as well as behavioral assays for cognitive function. The completion of this project will provide safety guidelines to facilitate the neurological and behavioral studies that are critical for understanding the mechanisms underlying post-acute sequelae. Source of Supplemental Funding: ORIP Title of Administrative Supplement 2: Role of type I IFN in regulating COVID-19 induced inflammation and pathogenesis Summary of the Supplement 2 This supplement will conduct a study using rhesus macaques to evaluate the effect of type I interferon (IFN) antagonist on COVID-19 disease severity. A wide range of viral, molecular, cellular, immunological, and clinical endpoints will be collected from the animals at serial timepoints. Many of these samples will be investigated histologically and/or via molecular and other approaches by two different labs to test and develop National Primate Research Center (NPRC) COVID-19 standard operating procedures and assess reproducibility. Samples will also be bio-banked as resources for future use by other researchers. Source of Supplemental Funding: NIAID Title of Administrative Supplement 3: Support of Yerkes National Primate Research Center Summary of the Supplement 3 The Yerkes National Primate Research Center at Emory University will conduct multiple facility and equipment enhancements in support of COVID-19 research in the ABSL-3 and BSL-3 facilities. The proposed equipment for purchase and use will provide optimal support for a large base of NIH-funded COVID-19 research projects at the Yerkes NPRC, ultimately contributing to the development of safe and effective vaccines and therapeutics for COVID-19. Source of Supplemental Funding: NIAID Title of Administrative Supplement 4: Using spatial transcriptomics and paired histopathology to identify tissue gene expression biomarkers of cognitive and physiological changes after SARS-CoV-2 infection in a rhesus macaque model Summary of the Supplement 4 This supplement will use histopathology analysis paired with spatial transcriptomics to investigate (i) the viral pathophysiology and (ii) the potential mechanism underlying post-acute sequelae (PASC) symptoms using SARS-CoV-2 infection in a rhesus macaque model. The novel approach proposed in this application will provide information that will help better elucidate the underlying causes of PASC. Results from this study will extend the field’s knowledge of SARS-CoV-2 pathophysiology and provide potential targets for developing much needed therapeutic interventions. Source of Supplemental Funding: ORIP

Parent Grant Number: P51OD011104 PI: Hamm, L Lee Title of Parent Project: Tulane National Primate Research Center Title of Administrative Supplement: Post-Acute COVID Sequelae in African Green Monkeys Summary of the Supplement 1 This supplement establishes a model in African green monkeys for the investigation of long-term effects of SARS-CoV-2 infection. For the proposed studies, the team will perform clinical, biologic, immunologic, virologic, behavioral, pulmonary, and telemetric studies at baseline and during SARS-CoV-2 infection in African green monkeys. The PIs will evaluate the status of active and transmissible infection to determine timepoints for the safe transfer of animals to a ABSL-2 environment that will facilitate studies of the longer-term consequences of SARS-CoV-2 infection. In addition, animals will also be administered the Pfizer vaccine to determine its potential as a therapeutic to modulate acute and post-acute infection phases. Source of Supplemental Funding: ORIP Title of Administrative Supplement 2: TNPRC Breeding Colony Expansion in Support of COVID-19 Research Summary of the Supplement 2 The project will add an enclosure unit to house additional specific-pathogen-free rhesus macaques and provide financial support for population expansion. The proposed enclosure has been designed to maximize capacity and flexibility with novel and proven environmental enhancement components. The improvement will expand the specific-pathogen-free rhesus macaque research infrastructure to assure these colonies are sustainable and able to provide well-characterized research models into the future, including providing animals for COVID-19 and pandemic-focused research. Source of Supplemental Funding: NIAID Title of Administrative Supplement 3: Improving Research Resources at the TNPRC to Support COVID-19 Research Summary of the Supplement 3 The Tulane National Primate Research Center (TNPRC) at Tulane University will enrich research resources for COVID-19 research through two specific resource improvements: expansion of specific-pathogen-free (SPF) rhesus macaque breeding colony housing infrastructure and the purchase of high-end laboratory instrumentation for BSL-2/3 laboratory space to support COVID-19 studies. Source of Supplemental Funding: NIAID Title of Administrative Supplement 4: Reprogramming of glucose metabolism and urea cycle in long COVID Summary of the Supplement 4 The Tulane National Primate Research Center at Tulane University will investigate the overarching hypothesis that virus-induced gut dysfunction, microbial translocation, and downstream interferon signaling induce dysregulation of metabolic pathways involved in glucose metabolism and the urea cycle in the liver. The studies will evaluate how these alterations contribute to major pathogenic features of COVID-19 infection and post-acute sequelae (PASC), particularly chronic fatigue, neurocognitive disturbances, and dysregulation of glucose utilization contributing to type 2 diabetes, which has increased prevalence in persons previously infected with SARS-CoV- 2. This project represents a novel inquiry into an exciting hypothesis that may provide new insights into novel and effective therapeutic strategies for SARS-CoV-2 infection and PASC. Source of Supplemental Funding: ORIP

Parent Grant Number: P51OD011133 PI: Schlesinger, Larry S Title of Parent Project: The Southwest National Primate Research Center – Overall Title of Administrative Supplement: Increasing the size of the specific-pathogen-free Indian rhesus macaque colony at the Southwest National Primate Research Center (SNPRC) for AIDS, COVID-19, and other infectious diseases research. Summary of the Supplement The goal of this project is to renovate a building to increase rhesus macaque breeding and holding space in support of SARS-CoV-2 research and other global pandemic emergencies. Source of Supplemental Funding: NIAID Title of Administrative Supplement 2: Significant expansion of the SNPRC ABSL-3 capability in the wake of COVID-19 Summary of the Supplement 2 The Southwest National Primate Research Center at the Texas Biomedical Research Institute will renovate and equip a recently decommissioned ABSL-3 facility, thus increasing ABSL-3 capacity for COVID-19 research. Source of Supplemental Funding: NIAID Title of Administrative Supplement 3: To better understand impact of long-term SARS-CoV-2 infection in a NHP (baboon) model Summary of the Supplement 3 The goal of this project is to characterize the long-terms health effects of COVID-19 infection in baboons and establish it as an animal model for studying post-acute sequelae of COVID-19. Various parameters relevant to long-term health effects will be measured, including viral RNA in plasma, urine, and lymphoid tissue; immune responses; lung function; chest radiograph; and electrocardiogram. This project will validate baboons as an animal for studying post-acute sequelae. Source of Supplemental Funding: ORIP Title of Administrative Supplement 4: Mechanistic interrogation of the role of type I IFN pathway in protection from SARS-CoV-2 infection in nonhuman primates Summary of the Supplement 4 The goal of this project is to perform mechanistic experiments where the progression of viral infection, disease parameters, and cytokine responses will be compared between SARS-CoV-2-infected rhesus macaques (RMs), SARS-CoV-2-infected RMs treated with type I IFN-inhibiting antibody from the Nonhuman Primate Reagent Resource, and SARS-CoV-2-infected RMs treated with recombinant IFN alpha. These experiments will help to definitively address whether silencing type I IFN signaling at the time of infection results in more SARS-CoV-2 replication and progression to COVID-19. Source of Supplemental Funding: ORIP

Parent Grant Number: P51OD011092 PI: Barr-Gillespie, Peter G Title of Parent Project: Support for National Primate Research Center Title of Administrative Supplement 1: Novel Therapy for SARS-CoV-2 Virus Infection and Pathogenesis by Aerosol Delivery of Monoclonal Antibodies Summary of the Supplement 1 The purpose of this study is to evaluate neutralizing monoclonal antibodies that possess high specificity and potency as a post-exposure prophylaxis for SARS-CoV-2 in rhesus macaques by using a novel aerosol delivery system. The potential benefits of inhaled monoclonal antibodies for patients are the following: (1) this treatment can be administered at home, (2) a smaller amount of material would be required for administration compared to intravenous delivery, and (3) risks associated with intravenous delivery, such as infusion reactions, acute anaphylaxis, and serum sickness, would be avoided. Source of Supplemental Funding: ORIP Title of Administrative Supplement 2: Corral 9 renovation to support SPF NHP breeding Summary of the Supplement 2 The project will expand existing housing with a newly designed half-acre corral tied to existing infrastructure that will provide animals with varied enrichment options and include an introduction area to facilitate animal reintegration. The proposed corral redesign will increase breeding capacity of SPF rhesus macaques for research to respond to SARS-CoV-2 and future emerging pathogens. Source of Supplemental Funding: NIAID

Parent Grant Number: P51OD010425 PI: Sullivan, Sean D Title of Parent Project: Washington National Primate Research Center Title of Administrative Supplement: Impact of pre-existing SARS-CoV-2 immunity on vaccination against new variants Summary of the Supplement The objective of this project is to test the impact of pre-existing SARS-CoV-2 immunity with vaccination against new virus variants. Pre-immunity to an earlier variant of SARS-CoV-2 may enable the new vaccines to induce an even broader group of antibody responses against different variants. This pilot study will boost the pre-existing immunity of the pigtail macaques to the original D614G variant with a self-amplifying replicon RNA (or “repRNA”) vaccine. Source of Supplemental Funding: ORIP

Parent Grant Number: P51OD011107 PI: Mohapatra, Prasant Title of Parent Project: California National Primate Research Center Title of Administrative Supplement 1: California National Primate Research Center Summary of the Supplement 1 This is an administrative supplement from the California National Primate Research Center (CNPRC). This supplement will support expand breeding of rhesus macaques at CNPRC through alteration and renovations (A&R) and an increased breeding program to produce more infants. The A&R portion consists of repairs to half-acre outdoor corrals to ensure functionality. Breeding colony expansion includes acquiring young rhesus macaques from the Caribbean Primate Research Center (CPRC) for integration into the breeding colony. Support for per diem of the expanded breeding group, as well as additional staff to provide animal care, colony management, and veterinary care needs, is included. The project will assist in providing animals for COVID-19 and pandemic-focused research. Source of Supplemental Funding: NIAID Summary of the Supplement 2 The California National Primate Research Center at the University of California, Davis, will conduct an Operation Warp Speed therapeutic study designed to understand what neutralizing antibody titer is needed to ameliorate disease in an early postexposure SARS-CoV-2 nonhuman primate model, which represents people who have mild disease/outpatients. This information is needed to inform therapeutic human clinical trials that are currently being planned and will lay the foundation for future studies for testing efficacy later in infection, representing patients who are hospitalized with severe disease. Source of Supplemental Funding: NIAID Summary of the Supplement 3 The California National Primate Research Center at the University of California, Davis, will purchase steel overhead structures for two half-acre field corrals, which will support increased breeding to ensure a continued pipeline of rhesus macaques for COVID-19 research, as well as equipment for an ABSL-3 suite to support infectious disease research on SARS-CoV-2. Source of Supplemental Funding: NIAID Summary of the Supplement 4 The goal of this proposal is to understand post-acute sequelae COVID by establishing a rhesus macaque animal model with the syndrome and using this model to dissect immunological and virological determinants of PASC. The investigators also aim to determine the feasibility of transitioning SARS-CoV-2-infected rhesus macaques from ABSL-3 to ABSL-2 by delineating the kinetics of infectious and non-infectious viral shedding in the respiratory and GI tracts, as well as generating preliminary data on the fundamental pathobiology of post-acute sequelae COVID. Vaccination followed by monitoring of immune activation/dysregulation, cardiovascular function, and lung function will be performed to understand the impact of vaccination on alleviation of post-acute sequelae symptoms. Source of Supplemental Funding: ORIP

Parent Grant Number: P40OD024628 PI: Simmons, Joe H Title of Parent Project: Specific Pathogen Free Baboon Research Resource (SPFBRR) Title of Administrative Supplement: Specific Pathogen Free Baboon Research Resource (SPFBRR) Summary of the Supplement This project proposes to develop a novel vaccine platform that employs engineered exosomes. Investigators will test the efficacy of exosomes in eliciting B- and T-cell immunity, as well as long-term antibody production in baboons. The project will also expand the capabilities of the Specific Pathogen Free Baboon Research Resource as a source of an alternate NHP model, along with offering a platform and related services for testing vaccines and other therapeutics. Source of Supplemental Funding: ORIP

Parent Grant Number: P51OD011107 PI: Ackerman, Steven A. Title of Parent Project: Wisconsin National Primate Research Center Support Title of Administrative Supplement: Administrative Supplement: Wisconsin National Primate Research Center Support: Conversion to ABSL-3 Facilities in the WNPRC Quarantine Unit Summary of the Supplement 1 This administrative supplement supports establishment of a functional ABSL-3 facility at the Wisconsin National Primate Research Center (WNPRC). Funds cover installation of two BioBubble enclosures that meet ABSL-3 requirements and have the capability to support basic SARS-CoV-2 challenge studies with essential endpoints. Source of Supplemental Funding: NIAID Summary of the Supplement 2 The Wisconsin National Primate Reseach Center at the University of Wisconsin–Madison will renovate quarantine suites into ABSL-3 space though purchase and installation of two ready-to-use BioBubble containment enclosures, as well as associated equipment (i.e., imaging, molecular biology, diagnostic, necropsy) to support SARS-CoV-2 challenge studies. Source of Supplemental Funding: NIAID

Parent Grant Number: P51OD011107 PI: Martinez, Melween I Title of Parent Project: Caribbean Primate Research Center Title of Administrative Supplement: Contribute to the breeding expansion and to the genetic diversity at California NPRC Summary of the Supplement This administrative supplement supports the transfer of specific-pathogen-free rhesus macaques from the conventional colony of the Caribbean Primate Research Center to the California National Primate Research Center to expand breeding capabilities and the diversity of the genetic pool at the California National Primate Research Center. This expansion will assist COVID and pandemic-focused research. Source of Supplemental Funding: NIAID

Parent Grant Number: U42OD010442 PI: Deepak Kushal Title of Parent Project: Establishment of a SPF Rhesus Macaque Colony Title of Administrative Supplement: PCR and antibody screening for SARS-CoV-2 in the SNPRC rhesus macaque colony Summary of the Supplement The purpose of this administrative supplement is to screen the entire Southwest National Primate Research Center (SNPRC) U42 rhesus macaque colony for both SARS-CoV-2 virus and antibodies using established approaches and to develop faster and less expensive in-house tests for SARS-CoV-2. The methods and results of this work at SNPRC will be disseminated to other primate centers maintaining SPF macaque breeding colonies. SNPRC will implement and develop methods for SARS-CoV-2 surveillance in the SNPRC SPF rhesus macaque breeding colony, allowing the detection and mitigation of a SARS-CoV-2 outbreak in the colony. Source of Supplemental Funding: ORIP

Parent Grant Number: U42OD011123 PI: Charlotte Hotchkiss (contact); Sally Thompson-Iritani Title of Parent Project: WaNPRC Macaca nemestrina SPF Breeding Colony Title of Administrative Supplement: Development of a COVID-19 Testing Program for SPF M. nemestrina Summary of the Supplement The purpose of this administrative supplement is to ensure that the current COVID-19 pandemic does not negatively affect the health of pigtail macaques within the SPF breeding colony, affect the health of individuals who work with these animals, or interfere with the usefulness of pigtail macaques as models for HIV/AIDS research or for COVID-19 research with surplus animals. The Washington National Primate Research Center (WaNPRC) will develop and validate virus and antibody tests for macaque coronaviruses, including SARS-CoV-2 and seasonal coronaviruses in pigtail macaques; determine the most efficient and accurate sampling and testing methods; and screen animals within the SPF pigtail macaque colony. The methods and results of this work at WaNPRC will be disseminated to other primate centers maintaining SPF macaque breeding colonies. Source of Supplemental Funding: ORIP

Parent Grant Number: U42OD010990-20W1 PI: Jeffrey Roberts Title of Parent Project: Production of Pedigreed SPF Rhesus Macaques Title of Administrative Supplement: California National Primate Research Center Summary of the Supplement The purpose of this administrative supplement is to expand the viral agents excluded for level 1 and 2 SPF macaque colonies to include SARS-CoV-2 as SPF NHP macaque populations are at risk for COVID-19. The California National Primate Reserach Center (CNPRC) will implement and develop methods for SARS-CoV-2 surveillance in the CNPRC SPF rhesus macaque breeding colony, allowing the detection and mitigation of a SARS-CoV-2 outbreak in the colony. The methods and results of the work will be disseminated to other primate centers maintaining SPF macaque breeding colonies through the NPRC Pathogen Detection Working Group and via ongoing interactions with ORIP program staff. Source of Supplemental Funding: ORIP

Parent Grant Number: U42OD011023 PI: Joyce Kimberly Cohen Title of Parent Project: Maintenance of the SPF Breeding Colonies at Yerkes National Primate Research Center Title of Administrative Supplement: Maintenance of the SPF Breeding Colonies at Yerkes National Primate Research Center Summary of the Supplement The purpose of this administrative supplement is to add screening for evidence of SARS-CoV-2 infection by developing and implementing molecular and serologic methods for detecting SARS-CoV-2 infection and immunity in the SPF rhesus macaque colony at the Yerkes NPRC. The proposal will also add genetic screening which will define and determine the frequency of distinct ACE2 coding alleles within the colony. The methods and results of this work at Yerkes will be disseminated to other primate centers housing SPF macaque colonies. Source of Supplemental Funding: ORIP

Parent Grant Number: P40OD028116 PI: Diogo Magnani (contact); Kathleen Engelman Title of Parent Project: Nonhuman Primate Antibody Resource for Immune Cell Depletion Title of Administrative Supplement: Nonhuman Primate Antibody Resource for Immune Cell Depletion Summary of the Supplement The purpose of this administrative supplement is to create safe recombinant reference macaque immunoglobulin standards to facilitate the development and validation of reliable assays for the detection of pathogenic coronaviruses and antiviral antibodies in nonhuman primate (NHP) animal models of COVID. Specifically, this supplement will fund the generation of the following reagents: recombinant coronavirus-reactive rhesus monoclonal IgGs and NHP serum reference standards. These macaque reference antibody reagents will improve the performance and comparability of antibody-based assays for NHP models by facilitating serum assay development, proficiency training, and interlaboratory performance comparisons at NHP centers and laboratories. Source of Supplemental Funding: ORIP

Parent Grant Number: R24OD021324-05 PI: Betsy M Ferguson Title of Parent Project: Genomic sequencing to establish a macaque genotype and phenotype research resource Title of Administrative Supplement: Genomic and Immunogenetic Resource to Support SARS-CoV-2/COVID-19 Nonhuman Primate Research Summary of the Supplement The purpose of this administrative supplement is to extend a centralized resource (mGAP) to include the generation, analysis, and dissemination of genomic sequence variants from nonhuman primates used in SARS-CoV-2 studies (the new SARS-CoV-2 portal will be located within the mGAP website). The proposed work, in conjunction with the mGAP resource, will support studies to understand how host genetic variation influences vaccine and treatment efficacy. Source of Supplemental Funding: ORIP


Mutant Mouse Research and Resources Centers and Other Rodent Resources
Parent Grant Number: U42OD010924 PI: Magnuson, Terry R Title of Parent Project: A Carolina Center to Characterize and Maintain Mutant Mice Title of Administrative Supplement: A Carolina Center to Characterize and Maintain Mutant Mice Summary of the Supplement 1 The Center will archive and distribute several existing SARS-CoV-2 mouse models, accelerating the availability of these mouse strains and supporting the development and phenotypic analysis of the new strains to address limitations of the existing transgenic models for more rigorous study of infection and disease. The resources generated by the supplement will meet the urgent need of the biomedical community for expanded access to current SARS-CoV-2 mouse models and the creation of newer improved models to inform preclinical development and testing of vaccines and therapeutics. Source of Supplemental Funding: ORIP Summary of the Supplement 2 This project will create, validate, archive, and distribute new mouse models that address the critical need to more accurately model human susceptibility and infection with SARS-CoV-2 variants, as well as the emerging study of post-acute sequelae. An ongoing screen for SARS-CoV-2 susceptibility in the Collaborative Cross using SARS-CoV-2-MA10 revealed a wide range of susceptibility and disease severity across tested strains, from complete resistance to susceptibility greater than that observed with classical inbred mouse strains tested to date. The PI will conduct comprehensive phenotypic characterization of the new strains by examining tissue-specific expression of ACE2 versus mouse Ace2 in a diverse array of tissues relevant to disease and by analyzing all lines for susceptibility to virus replication and disease pathology upon exposure to different SARS-CoV- 2 strains, including recently emerged variants of public health significance. Source of Supplemental Funding: ORIP

Parent Grant Number: U42OD010921 PI: Lutz, Cathleen M (contact); Reinholdt, Laura G Title of Parent Project: The Mutant Mouse Resource and Research Center at The Jackson Laboratory Title of Administrative Supplement: The Mutant Mouse Resource and Research Center at The Jackson Laboratory Summary of the Supplement This project addresses clinical variation in COVID-19 patients using humanized hACE2 mouse models on variable genetic backgrounds. The PIs will characterize infectivity, phenotypic response, disease outcome, and transcriptome heterogeneity of hACE2 knock-in mice crossed with inbred Collaborative Cross (CC) founder strains. Eight CC founder strains that have significantly different genetic backgrounds and different responses to SARS-CoV-2 infection will be used. The generated mouse strains will be sent to the collaborator for viral infection assays; monitoring of overall health, weight loss/survival, and viral load in various tissues; and transcriptome analysis. Animal models and data will be shared with the research community. This project will provide a valuable set of mouse models for studying clinical variation of COVID-19 and post-infection sequelae. Source of Supplemental Funding: ORIP

Parent Grant Number: R24OD026440 PI: Greiner, Dale Leslie (contact); Brehm, Michael Allen; Emerson, Charles P; Luban, Jeremy; Shultz, Leonard Title of Parent Project: Immunogenicity of Human Stem Cell-Derived Beta Cells and Muscle Cells in Humanized Mice Title of Administrative Supplement: Live imaging of SARS-CoV-2 infection in novel humanized mice Summary of the Supplement The goal of this supplement is to use a panel of humanized mouse models developed by Dr. Leonard Shultz at The Jackson Laboratory to study the human immune response to viral infection. Dr. Shultz has generated new models of NSG mice expressing human ACE2. These mice will be engrafted with human umbilical cord blood CD34+ hematopoietic stem cells and then used to study clearance of SARS-CoV-2, variants that are continually emerging, and testing of human-specific therapies that will mitigate the pathology associated with COVID-19. Source of Supplemental Funding: ORIP

Parent Grant Number: P40OD011102 PI: Reinholdt, Laura G (contact); Lutz, Cathleen M Title of Parent Project: Special Mouse Strains Resource Title of Administrative Supplement: Special Mouse Strains Resource Summary of the Supplement The supplement will determine the infectivity, kinetics of infection, and tissue distribution across inbred mouse strains for SARS-CoV-2 variants of concern. The data generated will serve a dual function: (1) de-risking valuable NIH mouse resources by understanding and monitoring for SARS-CoV-2 infection in a variety of genetically diverse strains and (2) increasing understanding as to the most relevant inbred strains to use in modeling patient disease for COVID-19. An additional study aim will also test aged mice, which will broaden the analysis to assess the effects of aging on viral infection. Source of Supplemental Funding: ORIP

Parent Grant Number: U42OD012210 PI: Lloyd, KC Kent Title of Parent Project: Mutant Mouse Resource and Research Center at UC Davis Title of Administrative Supplement: Mutant Mouse Resource and Research Center at UC Davis Summary of the Supplement 1 The Center will generate urgently needed mouse models for SARS-CoV-2 and COVID-19 biomedical research. These models will utilize variety of human gene products affecting SARC-CoV-2 entrance into the cells, as well as other human gene products that play key roles in the host inflammatory and immune response to disease, and are potentially involved in the severity of COVID-19 in patients with comorbidities, such as diabetes. Therefore, this proposal will breed, validate, and distribute new knockin/knockout models of pathogenic coronaviruses, including SARS-CoV-2, suitable for studying the pathogenesis of these viruses and screening vaccines and therapeutics. Source of Supplemental Funding: ORIP Summary of the Supplement 2 The goal of this supplement is to develop humanized mouse models for studying COVID-19 and post-acute sequelae of COVID-19 (PASC) by generating polygenic humanized mouse models with hACE2/hTMPRSS2, hACE2/hTMPRSS2/hFURIN, and hACE2/hTMPRSS2/hFURIN/hDPP4, and intercrossing of extant monogenic models. After establishing the strains, the team will validate the pathophysiological effects and assess PASC in the polygenic humanized mouse models inoculated with the currently dominant circulating SARS-CoV-2 B.1.1.7 strain. Polygenic humanized mice will be distributed to the research community for COVID-19 research. This project will generate valuable humanized animal models and resources for studying COVID-19, including PASC. Source of Supplemental Funding: ORIP Summary of the Supplement 3 This project will use CRISPR/Cas9 genome editing in C57BL/6J;ACE2/TMPRSS2 mice to introduce five high-risk genetic coding and noncoding single nucleotide polymorphisms (SNPs) in genes regulating interferon signaling (Ifna10 and Plscr1), immunological and inflammatory response (Tyk2 and Ppp1r15a), and substrate-specific cell membrane transporter proteins (Slc6a20) shown by GWAS to be associated with increased illness in human populations. The proposed research will seek to gain a better understanding of host-specific genetic effects on SARS-CoV-2 infection susceptibility and COVID-19 disease. These new humanized SNP models and experimental data will be made readily available for use by other researchers through the MMRRCs. Source of Supplemental Funding: ORIP

Parent Grant Number: U42OD010918 PI: Franklin, Craig L (contact); James Amos-Landgraf Title of Parent Project: The Mutant Mouse Resource and Research Center at the University of Missouri Title of Administrative Supplement 1: Facilitation of Post-Acute Sequelae to COVID Studies in Mouse Models Summary of the Supplement 1 This supplement will assess the kinetics of infection of SARS-CoV-2 in established mouse models by conducting longitudal studies, using several routes of administration, varying complexity of the microbiome, and using three different virus variants. The investigators will also follow the kinetics of reinfection and cross-infection with SARS-CoV-2 variants and determine a time point for viral clearance so that standard operating procedures for transfer of mice to ABSL-2 facilities can be generated. Source of Supplemental Funding: ORIP Title of Administrative Supplement 2: Optimization of murine models of COVID-19 through gut microbiota manipulation Summary of the Supplement 2 The purpose of this administrative supplement is to refine and optimize mouse models for the study of SARS-CoV-2 infection (COVID-19). The proposed project will assess how increasing antigen exposure of mice through supplementation of standardized complex gut microbiotas with selected viral and bacterial agents will modulate the phenotype of this model. Results generated will be invaluable and immediately applicable to ongoing studies of the devastating COVID-19 pandemic, and mice developed will be immediately available to the biomedical research community. Source of Supplemental Funding: ORIP

Parent Grant Number: P40OD011062 PI: Elizabeth C. Bryda Title of Parent Project: Rat Resource and Research Center Title of Administrative Supplement 1: Generation of Novel Rat Models for the Study of SARS-CoV-2 and COVID-19 Summary of the Supplement 1 The Center will generate novel hACE2-expressing rat models for the study of pathogenesis and evaluation of vaccines and antiviral therapies for viruses like SARS-CoV-2 that use hACE2 for entry into host cells. Humanized rats will be generated by random integration and targeted knockin of human ACE2 in both inbred (F344) and outbred (SD) genetic backgrounds. These animals after preliminary characterization will be readily available to the broad scientific community. Summary of the Supplement 2 The specific objectives of this project are to further characterize the created F344-Tg(CAG-ACE2)057 rat strain by using inhalation exposure to test if there is evidence of post-acute sequelae of COVID-19 in this model and to investigate the effects of genetic background and comorbidities on infection susceptibility. This model will be available through the Rat Resource and Research Center to facilitate ready distribution to interested investigators. The availability of a new animal model will advance the understanding of COVID-19 and SARS-CoV-2 pathogenesis, as well as accelerate the development of vaccines and antiviral therapies. Source of Supplemental Funding: ORIP

Parent Grant Number: R24OD024617 PI: Melinda R Dwinell Title of Parent Project: Hybrid Rat Diversity Program Title of Administrative Supplement: Hybrid Rat Diversity Program – Humanized hACE2 rat resource for COVID research Summary of the Supplement The purpose of this administrative supplement is to develop a resource of engineered ACE2 humanized rat models, a key receptor for multiple human coronaviruses, including SARS-CoV and SARS-CoV-2, to meet the pressing challenges faced by COVID-19 and future similar outbreaks. The development of engineered ACE2 humanized rat models on two genetic backgrounds will enable clinical translation needed for treatment and prevention of human coronaviruses including SARSCoV-2. Source of Supplemental Funding: ORIP

Parent Grant Number: UM1OD023222-09 PI: Braun, Robert E Title of Parent Project: The Jackson Laboratory Knockout Mouse Production and Phenotyping Project (JAX KOMP2) Title of Administrative Supplement: The Jackson Laboratory Knockout Mouse Production and Phenotyping Project (JAX KOMP2) Summary of the Supplement The Jackson Laboratory will develop the next generation of precision mouse models for mechanistic discovery of SARS-CoV-2 infection and therapeutic discovery of COVID-19 disease treatments. This new mouse model platform will incorporate diverse genetic backgrounds to characterize the variation in SARS-CoV-2 infection dynamics and the development of clinically relevant disease. The project will rapidly provide the research community with an urgently needed resource for linking the variability in COVID-19 disease outcome with underlying host genetic features and for developing precision therapies tailored to treat the individual patient. Source of Supplemental Funding: Common Fund/DPCPSI


Other ORIP Grantees
Parent Grant Number: R24OD030002 PI: Perrimon, Norbert Title of Parent Project: TRiP resources for modeling human disease Title of Administrative Supplement: TRiP resources for modeling human disease Summary of the Supplement This administrative supplement expands the transgenic tools offered by the TRiP in vivo Drosophila functional genomics resource by including high-confidence Drosophila orthologs of the human SARS-CoV-2 interactome, a recently described SARS-CoV-2-human protein-protein-interaction (PPI) network focused on how the virus hijacks host cells at the molecular level, thus disrupting normal cell function both during and after infection. This resource will allow researchers to easily knock down, knock out, or activate genes in the SARS-CoV-2 interactome, revealing the critical host factors and pathways and pointing to potential mechanisms of post-acute sequelae of SARS-CoV-2 infection. Source of Supplemental Funding: ORIP

Parent Grant Number: U42OD011140 PI: Randall Prather (contact); Kevin D. Wells Title of Parent Project: National Swine Resource and Research Center Title of Administrative Supplement: Swine Resource and Research Center COVID Administrative Supplement Summary of the Supplement 1 The Center will generate a large animal model (pig) that recapitulates human symptoms associated with SARS viruses that use angiotensin converting enzyme 2 (ACE2) as an entry receptor. This project will produce pigs that harbor a fully functional, human ACE2. The immediate application of this large-animal model is related to near-term testing of devices, strategies, and therapies in the context of translational medicine. In the long term, this model will be used to further the understanding of SARS biology and the host response. Summary of the Supplement 2 This administrative supplement is supporting a new improved strategy to develop humanized pig model with transgene hACE2 as a large-animal model for COVID-19 research and development of treatments. Investigators will create hACE2 cDNA as the transgene and introduce it into the pig genome in cultured primary cells. The hACE2 cDNA will be inserted into exon 2 of porcine ACE2. Somatic cell nuclear transfer (SCNT) will be used to generate transgenic pig with hACE2 transgene and select genotype as founder lines based on spatial expression of the transgene and SARC-CoV-2 susceptibility. Breeding colony will be established, and pig COVID model will be characterized. Source of Supplemental Funding: ORIP

Parent Grant Number: R24OD022005 PI: Hugo J Bellen Title of Parent Project: A Human cDNA Library for Functional Gene Replacement in Drosophila Title of Administrative Supplement: A Comprehensive Human cDNA Library for Functional Gene Replacement in Drosophila Summary of the Supplement 1 The purpose of this administrative supplement is to generate a comprehensive library of transgenic and mutant Drosophila for studies of COVID-19. The proposed project will allow investigators to study the 26 protein-coding genes for SARS-CoV-2 by expressing them in Drosophila to assess the consequences of their expression. This proposal will also create tools to study over 300 human genes that have been shown to bind to viral proteins that may be involved in COVID-19. Summary of the Supplement 2 The overall purpose of this administrative supplement is to develop and systematically characterize transgenic fly strains (resources) for studying molecular mechanism underlying SARS-CoV-2 infection, viral-host protein interactions, and post-acute sequelae of COVID-19. This project is built upon a previous administrative supplement project funded by ORIP in 2020, which led to the generation of 451 COVID-19 relevant fly stocks carrying different components of SARS-CoV-2 or host proteins potentially interacting with SARS-CoV-2 proteins. This project will provide valuable and comprehensive list of “off-the-shelf” fly stocks for the research community to conduct unbiased forward genetic screen or hypothesis drive research on molecular mechanisms underlying COVID-19. Source of Supplemental Funding: ORIP

Parent Grant Number: R24OD024624 PI: Gary Joseph Patti Title of Parent Project: A comprehensive resource for high-throughput profiling of worm and zebrafish metabolomes Title of Administrative Supplement: A comprehensive resource for high-throughput profiling of worm and zebrafish metabolomes Summary of the Supplement The purpose of this project is to develop a resource that will enable researchers to use model organisms to rapidly screen drug targets and potential disease mechanisms. This project will facilitate the application of metabolomics to COVID-19-related studies in worms and zebrafish. The metabolic dysfunction uncovered in human patients will be mapped to the worm and zebrafish metabolomes by using technologies developed in the parent award. Comparing metabolic changes from each of these models to reference COVID-19 pathways will improve understanding of which disease processes contribute to COVID-19 pathology. Source of Supplemental Funding: ORIP

Parent Grant Number: R24OD018559 PI: Keith Chi Cheng Title of Parent Project: Groundwork for a Synchrotron MicroCT Imaging Resource for Biology (SMIRB) Title of Administrative Supplement: Groundwork for a Synchrotron MicroCT Imaging Resource for Biology (SMIRB) Summary of the Supplement The purpose of this administrative supplement is to support an equipment upgrade (MicroCT), thus improving resolution when producing a 3D form of histology (X-ray histotomography) of lung tissues from a humanized mouse model of COVID and human autopsy samples. This technology, developed in the parent R24 grant, will help to characterize the cellular and tissue geometries of COVID-19-associated acute respiratory distress syndrome (ARDS) pneumonia (COVID-19 pandemic’s most common cause of death). Source of Supplemental Funding: ORIP

December 4, 2023

Updates and Current Research from ORIP Grantees

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Updates and Current Research from ORIP Grantees

SARS-CoV-2 and Coronavirus-Related Interactions (BioGRID)

Policies

Affiliated Websites