Epigenetics of HIV, Aging, and Sleep Deficiency
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Project Summary/Abstract Older people living with HIV (PLWH) are at high risk for multiple adverse geriatric outcomes, including cognitive impairment. Cognitive impairment in older PLWH has been closely linked to CNS immune activation, but the cellular mechanisms driving this abnormal CNS immune activity remain unknown, and the role of epigenetic modifications in promoting CNS immune activation in PLWH has not been examined. Epigenetic changes provide a potential link between HIV, sleep deficiency, and aging-induced CNS immune activation. DNA methylation (DNAm), one of the main and best-characterized epigenetic modifications, is affected by normal aging, by HIV infection, and by sleep deficiency, which is highly prevalent in PLWH. While DNAm changes can occur anywhere in the genome, the epigenetic integrity of circadian clock genes has been specifically tied to maintaining immune homoeostasis in the brain, and the epigenetic disruption of these genes has been associated with neuroinflammation. Our preliminary studies in PLWH demonstrate that DNAm of circardian clock genes within CNS-disease relevant monocytes is differentially altered in PLWH compared to controls, suggesting that these epigenetic changes may contribute to CNS disease in older PLWH. For this proposed administrative supplement to the Yale Pepper Center parent grant, we will measure epigenetic changes in circadian clock genes in both peripheral blood and in cerebrospinal fluid (CSF) immune cells from older PLWH and matched controls, using tissue already biobanked as part of the Yale HARC cohort study of PLWH. In AIm 1, we will assess whether epigenetic changes in circadian-clock genes associate with soluble CSF markers of CNS immune activation. In Aim 2, we will assess whether sleep deficiency associates with epigenetic dysregulation of circadian clock genes, and with CNS immune activation in PLWH. This work will be performed by a multidisciplinary team from the Yale Pepper Center and Weill Cornell, with diverse expertise in aging, HIV neurology, epigenetics, sleep, and biostatistics. The results will inform future interventions to improve sleep deficiency and prevent adverse neurocognitive and functional outcomes in older PLWH.
The overarching objective of the Leadership and Administrative Core (LAC) is to advance the scientific knowledge base of multifactorial geriatric conditions. The LAC, which is led by two board-certified geriatric physician investigators with complementary expertise, is responsible for strategic planning, organization, administrative operations and evaluation of the OAIC research and training program. A special effort is devoted to ensure the cohesion of the Center and maintenance of an interdisciplinary and translational research focus on the common research theme, which is "the investigation of multifactorial geriatric conditions". The key LAC tasks are achieved by the Core Leader (Dr. Thomas Gill), Co-Leader (Dr. Terri Fried), Associate Leader, two Administrators, and three committees: the Executive Committee, the Internal Advisory Committee, and the External Advisory Committee. The LAC has gained much experience, knowledge, and understanding of OAIC operations over its 25 years of continuous funding, including the past 15 years under the P30 mechanism. We will build on the strong existing collaborative relationships and cumulative expertise as we enter our next funding cycle. The Specific Aims of the LAC are to: (1) oversee the coordination, integration, and administration of all aspects of the OAIC, including the utilization of core resources, and foster collaborations with other research and training programs that will help to accomplish the OAIC goals; (2) promote the conduct of academically productive, innovative, high impact, and clinically safe research by Pepper Scholars, other early-stage investigators, Pilot/Exploratory Studies (PESs), Resource Cores, and External Projects; (3) ensure the independent review and oversight of OAIC research and the training of Pepper Scholars and other early-stage investigators; (4) foster the career development of junior faculty/other trainees from multiple disciplines into independent investigators and academic leaders in aging research; (5) recruit and encourage outstanding early-stage investigators and senior faculty to focus their research on aging, particularly multifactorial geriatric conditions, with an emphasis on translation between basic and clinical research; (6) identify and facilitate productive collaborations with other OAICs and institutions; and (7) monitor university, government and fiscal matters, ensure the preparation of necessary progress reports and administrative documents relating to the award, and collaborate with the NIA project office and Coordinating Center on OAIC activities. Taken together, the LAC provides support for planning, organizational, evaluation, and administrative activities relating to the other Cores and to the OAIC as a whole. The LAC is responsible for monitoring, stimulating, sustaining, evaluating, and reporting progress toward the overall goals of the Yale OAIC.
