CMV and CMV-Immune Responses in Geriatric Conditions Post-Kidney Transplant (CMV-GeriKT)
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ABSTRACT Chronic infections like cytomegalovirus (CMV) may contribute to both cognitive and physical function decline in older adults and have been implicated in the development of Alzheimer's Disease (AD), vascular dementia, and frailty. Due to immune senescence and immune suppression, older Kidney Transplant (KT) recipients ≥50 years, are at especially high risk of early and frequent reactivations of latent CMV and may fail to reconstitute CMV-specific cell-mediated immunity (CMV-CMI), leading to high rates of CMV disease. This research will investigate for the first time the role of CMV and CMV-CMI reconstitution in cognitive and physical functional decline in KT recipients. This research is relevant to the NIA mission because it will advance the understanding of the critical mechanisms driving CMV-related aging in older adults by studying the impact of CMV on decline in cognitive and physical function, AD, and frailty. This proposal's central hypothesis is that inflammation secondary to CMV replication may explain the mechanism by which CMV may contribute to cognitive and physical function decline, AD, and progression of frailty. This hypothesis will be tested through the following specific aims: 1) To quantify the association of CMV serostatus with trajectories of cognition and physical function in an existing Functional Assessment of Renal Disease (FAIR) cohort of older KT recipients; 2) To assess the relationship of CMV-CMI reconstitution with trajectories of cognitive and physical function and frailty in a newly established Colorado cohort of CMV+ older KT recipients; 3) To investigate the relationship of inflammatory markers with trajectories of cognition and physical function among CMV+ and CMV- KT recipients at 1-year post-KT in Colorado cohort. This approach is innovative because it: 1) allows the first investigation of the relationship of CMV, with the trajectories of cognitive and physical function among older KT recipients, and 2) may identify the role of CMV-CMI and inflammation driving the relationship of CMV with cognitive and physical function decline. This project is significant because it has the potential to improve health outcomes for older KT recipients. Complimentary to the proposed research plan, a five-year mentored career development training plan has been devised that incorporates research training in geriatrics and viral immunology. The candidate is co- mentored by internationally recognized experts in gerontology, viral immunology, kidney transplantation, and epidemiology. The candidate's long-term career goal is to become an independent investigator studying immune protection in the context of chronic viral infections with geriatric outcomes.
