Mosaic loss of Y chromosome in blood and heart failure

项目摘要/摘要 最近的技术进步表明，体细胞DNA突变随着年龄的增长而积累，而且它们是 非常普遍。血液中Y染色体嵌合体丢失(MLOY)是最常见的受精卵后 人类的突变。流行病学研究已将MLOY与全因死亡率和年龄倍数联系在一起。 相关疾病。然而，目前尚不清楚mLOY与疾病之间是否存在因果联系。 父母资助正在使用小鼠模型来评估mLOY在心力衰竭中的影响。 水平。行政副刊将建立在与家长共同开发的概念和技术的基础上 格兰特探索mloy在认知衰退中的因果作用，并定义其机制的各个方面。 流行病学研究表明，血液中的mLOY与阿尔茨海默病和相关痴呆有关 (ADRD)。然而，还没有研究表明mLOY是否与认知衰退有机械联系。至 为了解决这一知识差距，我们要求一年的行政补充来执行探索性 双侧颈动脉狭窄(BCAS)血管贡献模型的实验mLOY分析 认知障碍和痴呆症(VCID)。BCAS模型引起脑低灌注率和铅 导致脑白质损伤、神经退行性变以及由此导致的认知能力下降。BCAS研究的理论基础 1)mLOY与VCID密切相关的脑血管病变，包括短暂性脑血管病变 脑缺血发作、前脑动脉闭塞和狭窄及脑梗塞；2)BCAS模型 有较快的扭亏为盈，适合这一年的补充。我们预计这项新的研究 由行政副刊资助的将扩大我们的试点数据，显示衰老的mLOY小鼠(15个月 BMT后)在Y迷宫和新奇物体识别测试中有短期工作记忆缺陷。因此，在 在拟议的研究中，我们将1)在BCAS模型中调查mLOY是否促进认知能力下降 VCID使用多个独立的mLOY模型，以及2)调查是否损害了衰老的清除 由mLOY免疫细胞产生的细胞导致认知功能下降。

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.