Selected Grantee Publications
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- Cardiovascular
- Women's Health
Murine MHC-Deficient Nonobese Diabetic Mice Carrying Human HLA-DQ8 Develop Severe Myocarditis and Myositis in Response to Anti-PD-1 Immune Checkpoint Inhibitor Cancer Therapy
Racine et al., Journal of Immunology. 2024.
Myocarditis has emerged as a relatively rare but often lethal autoimmune complication of checkpoint inhibitor (ICI) cancer therapy, and significant mortality is associated with this phenomenon. Investigators developed a new mouse model system that spontaneously develops myocarditis. These mice are highly susceptible to myocarditis and acute heart failure following anti-PD-1 ICI-induced treatment. Additionally, the treatment accelerates skeletal muscle myositis. The team performed characterization of cardiac and skeletal muscle T cells using histology, flow cytometry, adoptive transfers, and RNA sequencing analyses. This study sheds light on underlying immunological mechanisms in ICI myocarditis and provides the basis for further detailed analyses of diagnostic and therapeutic strategies. Supported by ORIP (U54OD020351, U54OD030187), NCI, NIA, NIDDK, and NIGMS.
Pigs in Transplantation Research and Their Potential as Sources of Organs in Clinical Xenotransplantation
Raza et al., Comparative Medicine. 2024.
https://pubmed.ncbi.nlm.nih.gov/38359908/
The pig has now gained importance as a potential source of organs for clinical xenotransplantation. When an organ from a wild-type (i.e., genetically unmodified) pig is transplanted into an immunosuppressed nonhuman primate, a vigorous host immune response causes hyperacute rejection (within minutes or hours). This response has been largely overcome by (1) extensive gene editing of the organ-source pig and (2) administration to the recipient of novel immunosuppressive therapy based on blockade of the CD40/CD154 T-cell costimulation pathway. The combination of gene editing and novel immunosuppressive therapy has extended life-supporting pig kidney graft survival to greater than 1 year and of pig heart survival to up to 9 months. This review briefly describes the techniques of gene editing, the potential risks of transfer of porcine endogenous retroviruses with the organ, and the need for breeding and housing of donor pigs under biosecure conditions. Supported by ORIP (P40OD024628) and NIAID.
De Novo Variants in FRYL Are Associated With Developmental Delay, Intellectual Disability, and Dysmorphic Features
Pan et al., The American Journal of Human Genetics. 2024.
https://www.cell.com/ajhg/fulltext/S0002-9297(24)00039-9
FRY-like transcription coactivator (FRYL) belongs to a Furry protein family that is evolutionarily conserved from yeast to humans, and its functions in mammals are largely unknown. Investigators report 13 individuals who have de novo heterozygous variants in FRYL and one individual with a heterozygous FRYL variant that is not confirmed to be de novo. The individuals present with developmental delay; intellectual disability; dysmorphic features; and other congenital anomalies in cardiovascular, skeletal, gastrointestinal, renal, and urogenital systems. Using fruit flies, investigators provide evidence that haploinsufficiency in FRYL likely underlies a disorder in humans with developmental and neurological symptoms. Supported by ORIP (U54OD030165), NHLBI, NICHD, and NCATS.
Effect of Hormone Replacement Therapy on Amyloid Beta (Aβ) Plaque Density in the Rhesus Macaque Amygdala
Appleman et al., Frontiers in Aging Neuroscience. 2024.
https://www.frontiersin.org/articles/10.3389/fnagi.2023.1326747/full
Amyloid beta plaque density is associated with Alzheimer’s disease. In this study, the authors examined its concentration in aged female nonhuman primates’ cerebrospinal fluid, as well as in the amygdala, an area of the brain involved with emotion and memory. They set out to test the hypothesis that estrogen hormone replacement therapy can beneficially affect amygdala Aβ plaque density in “surgically menopausal” females (i.e., aged rhesus macaques that had undergone ovariectomy). Female rhesus macaques that received estrogen replacement therapy showed fewer amyloid plaques than those that did not receive the hormone. This effect was observed regardless of the type of diet that the animals consumed. These findings suggest that hormone replacement might be a helpful treatment to consider for Alzheimer’s disease. Supported by ORIP (P51OD011092, R24OD011895, S10OD025002) and NIA.
Cytomegalovirus Infection Facilitates the Costimulation of CD57+CD28- CD8 T Cells in HIV Infection and Atherosclerosis via the CD2–LFA-3 Axis
Winchester et al., Journal of Immunology. 2024.
https://pubmed.ncbi.nlm.nih.gov/38047900/
People with HIV are at increased risk of developing atherosclerosis and other cardiovascular diseases, and HIV coinfection with cytomegalovirus (CMV) is associated with immune activation and inflammation. In this study, researchers explored the role of the CD2–LFA-3 axis in driving activation and proliferation of CD57+CD28- CD8 T cells using clinical samples from patients with or without HIV. They propose a model in which CMV infection is linked to enhanced CD2 expression on the T cells, enabling the activation via LFA-3 signals and potentially leading to cardiopathogenic interactions with vascular endothelial cells that express LFA-3. This work provides a potential therapeutic target in atherosclerosis development and progression, especially for people with HIV. Supported by ORIP (P51OD011132, U24OD011023) and NIAID.
The Power of the Heterogeneous Stock Rat Founder Strains in Modeling Metabolic Disease
Wagner et al., Endocrinology. 2023.
https://pubmed.ncbi.nlm.nih.gov/37882530/
Metabolic diseases are a host of complex conditions, including obesity, diabetes mellitus, and metabolic syndrome. Endocrine control systems (e.g., adrenals, thyroid, gonads) are causally linked to metabolic health outcomes. In this study, investigators determined novel metabolic and endocrine health characteristics in both sexes of six available substrains similar to the N/NIH Heterogeneous Stock (HS) rat founders. This deep-phenotyping protocol provides new insight into the exceptional potential of the HS rat population to model complex metabolic health states. The following hypothesis was tested: The genetic diversity in the HS rat founder strains represents a range of endocrine health conditions contributing to the diversity of cardiometabolic disease risks exhibited in the HS rat population. Supported by ORIP (R24OD024617), NHLBI, NIGMS and NIDDK.
Biphasic Decay of Intact SHIV Genomes Following Initiation of Antiretroviral Therapy Complicates Analysis of Interventions Targeting the Reservoir
Kumar et al., PNAS. 2023.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10614214/
The latent HIV-1 reservoir persists with antiretroviral therapy (ART), and assays for quantifying intact proviruses in nonhuman primate models are needed. Researchers used a simian–human immunodeficiency virus (SHIV) intact proviral DNA assay to describe viral decay during the first year of ART in female rhesus macaques. Their results suggest that intact SHIV genomes in circulating CD4+ T cells undergo biphasic decay during the first year of ART, with a rapid first phase and a slower second phase. These findings can provide insight for future studies using SHIV models, as well as new cure interventions. Supported by ORIP (R01OD011095) and NIAID.
Zebrafish as a High Throughput Model for Organ Preservation and Transplantation Research
Da Silveira Cavalcante et al., The FASEB Journal. 2023.
https://faseb.onlinelibrary.wiley.com/doi/10.1096/fj.202300076R
Organ transplantation increases the quality of life and life expectancy of patients with chronic end-stage diseases, but the preservation of organs for transplantation remains a significant barrier. In the current study, researchers demonstrate the value of zebrafish as a high-throughput model organism in the fields of solid-organ preservation and transplantation, with a focus on heart preservation via partial freezing. Their techniques have the potential to advance research in the fields of cryobiology and solid-organ transplantation. Supported by ORIP (R24OD031955) and NHLBI.
Effects of Pulsatile Intravenous Follicle-Stimulating Hormone Treatment on Ovarian Function in Women With Obesity
Luu et al., Fertility and Sterility. 2023.
https://pubmed.ncbi.nlm.nih.gov/37276947/
By performing intravenous (IV) administration of pulsatile recombinant follicle-stimulating hormone (FSH), researchers established conditions for effective hypothalamic suppression in women with normal and high body mass index (BMI). In women with obesity, the treatment resulted in E2 and inhibin B levels comparable to those in normal-weight women. This work offers a potential strategy to mitigate some of the adverse effects of high BMI on fertility, assisted reproduction, and pregnancy outcomes. Supported by ORIP (K01OD026526), NIA, and NICHD.
Large-Scale Production of Human Blastoids Amenable to Modeling Blastocyst Development and Maternal-Fetal Crosstalk
Yu et al., Cell Stem Cell. 2023.
https://www.sciencedirect.com/science/article/abs/pii/S1934590923002850?via%3Dihub=
Human blastoids provide a valuable model to study early human development and implantation with reduced genetic heterogeneity between samples. Investigators reported a protocol for efficient generation of high-fidelity human blastoids from naïve pluripotent stem cells. The similarities between blastoids and blastocysts in signaling activities—demonstrated using single-cell RNA sequencing—support the use of blastoids to model lineage differentiation and cavity formation. Additionally, endometrial stromal effects in promoting trophoblast cell survival, proliferation, and syncytialization during co-culture with blastoids demonstrated the capability to model maternal–fetal crosstalk. The protocol will facilitate broader use of human blastoids as an ethical model for human blastocysts. Supported by ORIP (S10OD028630) and others.