Programs and Activities Highlights
- Limited Competition: Development and Renovation of Facilities for Expanding the Breeding Capacity of Specific Pathogen Free Non-Human Primates to Support HIV/AIDS–Related Research (C06 Clinical Trial Not Allowed)
Nonhuman primates (NHPs) serve as a critical animal model for biomedical research, including HIV-related research. The COVID-19 pandemic and export bans from Asian countries exacerbated the existing NHP shortage. Despite NIH efforts to improve NHP availability, limited facility resources still hamper the safe and effective production of this animal model. To meet this urgent need, ORIP, in collaboration with the Office of AIDS Research, published a new notice of funding opportunity titled Development and Renovation of Facilities for Expanding the Breeding Capacity of Specific Pathogen Free Non-Human Primates to Support HIV/AIDS–Related Research. This funding opportunity is expected to expand the support of NHP breeding resources and increase the output of NHP models substantively and cost-effectively, addressing the urgent need of NHPs for HIV research.
- Site Visit to the Gladstone Institute
ORIP staff conducted a virtual site visit on November 13, 2023, to evaluate the progress of a construction award (C06RR018928) to the Gladstone Institute. This grant provided funding for the fit-out of animal facilities in the new laboratory building at the University of California, San Francisco, Mission Bay campus to support research on cardiovascular, neurological, viral, and immune diseases. The facility has supported 30 laboratories for animal studies since 2003 and enabled research funded by more than $145 million in NIH grants. Gladstone includes more than 500 researchers, including 2 Nobel laureates, and 80% of the faculty have benefitted from the animal facility. Gladstone has produced about 300 issued U.S. and foreign patents; one-third of these patents relate to animal models.
- Pre-Application Webinar for Non-Human Primate Facilities (PAR-24-033) and Biomedical Research Facilities (PAR-23-306)
ORIP held a pre-application webinar in December 2023 for two notices of funding opportunities: Development and Renovation of Facilities for Expanding the Breeding Capacity of Specific Pathogen Free Non-Human Primates to Support HIV/AIDS-related Research (C06 Clinical Trial Not Allowed) and Biomedical Research Facilities (C06 Clinical Trial Not Allowed). ORIP program staff presented a program overview; explained the goals and application structures of these funding opportunities to around 130 attendees; and answered questions regarding budget, timeline, and review. Follow-up questions sent by email also were answered by ORIP program staff.
- ORIP’s Construction Site Visits
Between October and December 2023, ORIP’s Division of Construction and Instruments performed site visits to eight facilities funded by construction grants. The final site visits to six of these facilities—including the animal facility at the Gladstone Institutes and the Cell Manipulation Core Facility at the Dana-Farber Cancer Institute—allowed ORIP to evaluate the impact, usage, and maintenance of these facilities during their 20-year beneficial occupancy periods. The other two were closeout site visits to two recently completed grants, which allowed ORIP to learn from these construction projects and assess the facility operation. The new Healthy Kentucky Research Building at the University of Kentucky supports research on health disparities, with an emphasis on vascular diseases. The Duke Human Vaccine Institute’s current Good Manufacturing Practice facility is at the forefront of efforts related to rapid responses and pandemic preparedness in helping the National Institute of Allergy and Infectious Diseases produce influenza and pan-coronavirus vaccine candidates.
- ORIP R24 Modern Equipment Program for Innovation of Biomedical Research Operations
ORIP established the R24 Modern Equipment Program in 2022 to complement the S10 Shared Instrumentation Programs. The R24 program supports the acquisition and installation of research-enabling equipment to enhance operations in shared biomedical research facilities. To broaden the program impact, ORIP formed a collaboration with NIGMS for co-funding. This coalition resulted in 27 equipment awards in fiscal year 2023 (FY23), an increase of 6 grants from fiscal year 2022 (FY22). Awards for research capability–building in resource-limited institutions, such as the Institutional Development Award (IDeA), also increased, which resulted in 9 grants being awarded to IDeA institutions in FY23, compared to 4 awards in FY22.
Read more in the archive.
Research Highlights from Investigators Using ORIP-Supported Instrumentation
- Epigenetic Dysregulation From Chromosomal Transit in Micronuclei
The authors reported a mechanistic link between epigenetic alterations and chromosomal instability induced during their transit in micronuclei, both being hallmarks of advanced and metastatic cancers. It was demonstrated that the landscape of histone post-translational modifications was profoundly changed due to missegregation of mitotic chromosomes, their sequestration in micronuclei, and subsequent rupture of the micronuclear envelope. The transcriptional redistribution was attributed to micronuclei’s strong positional bias with increased promoter accessibility. The continuous formation and reincorporation of micronuclei promotes epigenetic reprogramming and heterogeneity in cancer.
- Association of Age at Menopause and Hormone Therapy Use With Tau and β‑Amyloid Positron Emission Tomography
To understand the predominance (70%) of women among individuals with Alzheimer’s disease, the investigators studied regional tau and β-amyloid (Aβ) in relation to age at menopause and hormone therapy (HT) in postmenopausal women and age-matched men using positron emission tomography. The study demonstrated that females exhibited higher tau deposition compared with age-matched males, particularly in the setting of elevated Aβ; earlier age at menopause and late initiation of HT were associated with increased tau vulnerability. This study suggests women with these conditions may be at higher risk of pathological burden. The article also calls for a mechanistic understanding of menopause and dementia to help clarify the risk-benefit controversies around HT, which could be explored in future studies. This article was highlighted in various news outlets.
- Broad Receptor Tropism and Immunogenicity of a Clade 3 Sarbecovirus
Investigators showed that the S glycoprotein of the clade 3 sarbecovirus PRD-0038 in the African Rhinolophus bat has broad ACE2 (angiotensin-converting enzyme 2) usage and that receptor-binding domain (RBD) mutations further expand receptor promiscuity and enable human ACE2 utilization. They generated a cryogenic electron microscopy structure of the RBD bound to ACE2, explaining receptor tropism and highlighting differences between SARS-CoV-1 and SARS-CoV-2. PRD‑0038 S vaccination elicits greater titers of antibodies cross-reacting with vaccine-mismatched clade 2 and clade 1a sarbecoviruses, compared with SARS-CoV-2. These findings underline a potential molecular pathway for zoonotic spillover of a clade 3 sarbecovirus, as well as the need to develop pan-sarbecovirus vaccines and countermeasures.
- Intestinal Microbiota Controls Graft-Versus-Host Disease Independent of Donor–Host Genetic Disparity
Allogeneic hematopoietic stem cell transplantation is a curative therapy for hematopoietic malignancies and non-malignant diseases, but acute graft-versus-host disease (GVHD) remains a serious complication. Specifically, severe gut GVHD is the major cause of transplant-related mortality. Here, the authors show that genetically identical mice, sourced from different vendors, had distinct commensal bacterial compositions, which resulted in significantly discordant severity in GVHD. These studies highlight the importance of pre-transplant microbiota composition for the initiation and suppression of immune-mediated pathology in the gastrointestinal tract, demonstrating the impact of non-genetic environmental determinants on transplant outcome.
- First-in-Human ImmunoPET Imaging of COVID-19 Convalescent Patients Using Dynamic Total-Body PET and a CD8-Targeted Minibody
Developing noninvasive methods for in vivo quantification of T cell distribution and kinetics is important because most T cells reside in the tissue. Investigators presented the first use of dynamic positron emission tomography (PET) and kinetic modeling for in vivo measurement of CD8+ T cell distribution in healthy individuals and COVID-19 patients. Kinetic modeling results aligned with the expected T cell trafficking effects. Tissue-to-blood ratios were consistent with model net influx rates and flow cytometry analysis. These results provide a promising platform for using dynamic PET to study the total-body immune response and memory.
Read more in the archive.
