Mosaic loss of Y chromosome in blood and heart failure

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PROJECT SUMMARY/ABSTRACT Recent technological advances indicate that somatic DNA mutations accumulate with age and that they are remarkably prevalent. Mosaic loss of the Y chromosome (mLOY) in blood is the most common post-zygotic mutation in humans. Epidemiological studies have associated mLOY with all-cause mortality and multiple of age- associated diseases. However, it is unknown whether there is a causal connection between mLOY and disease. The parental grant is employing murine models to assess the impact of mLOY in heart failure at a mechanistic level. The Administrative Supplement will build upon the concepts and technology developed with the parent grant to explore the causal role of mLOY in cognitive decline and define aspects of mechanism. Epidemiological studies have associated mLOY in blood with Alzheimer’s Disease and Related Dementias (ADRD). However, no work has addressed whether mLOY is mechanistically linked to cognitive decline. To address this gap in knowledge, we request a one-year administrative supplement to perform exploratory analyses of experimental mLOY in the Bilateral Carotid Artery Stenosis (BCAS) model of Vascular Contributions to Cognitive Impairment and Dementia (VCID). The BCAS model gives rise to cerebral hypoperfusion and leads to white matter damage, neurodegeneration and consequent cognitive decline. The rationale for the BCAS study is: 1) mLOY is associated with cerebrovascular pathologies closely associated with VCID, including transient ischemic attacks, occlusion and stenosis of pre-cerebral arteries and cerebral infarction, and 2) the BCAS model has relatively rapid turnaround that is suitable for this one-year supplement. We anticipate that the new research funded by the Administrative Supplement will extend our pilot data showing that aging mLOY mice (15 months after BMT) had short-term working memory deficits in the Y-maze and novel object recognition tests. Thus, in the proposed studies, we will 1) investigate whether mLOY promotes cognitive decline in the BCAS model of VCID using multiple independent models of mLOY, and 2) investigate whether impaired clearance of senescent cells by mLOY immune cells contributes to cognitive decline.