Reducing vascular cognitive impairment within and across generations by epigenetic conditioning

项目摘要 继发于血管对认知障碍和痴呆的贡献的神经认知障碍（VCID） 对我们的老龄化人口造成毁灭性的损失，迄今为止，有效的治疗方法仍然难以捉摸。表观遗传学- 在这方面，基础疗法有希望，因为越来越多的证据继续证明表观遗传 响应于不同模式的“积极压力”诱导有益的、抗病的表型 （`eustress '）。这些深刻的发现表明，重新编程激活和抑制一系列广泛的 在没有任何外源性药物的情况下， 治疗事实上，我们实验室最近使用成熟的VCID模型的研究结果表明， 用短暂的无害的全身性缺氧（RHC）调节小鼠可防止体内记忆丧失， 保留海马突触可塑性离体，由三个月的慢性脑灌注不足引起 继发于双侧颈动脉狭窄。此外，我们发现成年的第一代后代 在交配前用RHC处理的小鼠中，也表现出这些相同的抗VCID表型-在 没有任何直接治疗。因此，本建议是建立在总体假设的基础上的， 基于表观遗传学的治疗可以在代内和跨代预防与VCID相关的认知丧失。 目标1中的研究旨在确定上述代际保护是否会影响认知能力， 由父母RHC引起的损伤需要父母双方或仅父亲或母亲治疗。的 这些研究的结果将为未来的生殖细胞表观遗传变化研究提供信息，这些变化最终成为这一研究的基础。 诱导的有益表型的转移。目标2中的研究旨在开始解开表观遗传学 负责保护小鼠免受VCID相关认知障碍的调节机制 直接用RHC处理，特别关注组蛋白脱乙酰酶3（HDAC 3）及其在 基因的转录调控有助于RHC介导的痴呆恢复。这些研究结果 将开始建立一个分子框架，用于研究基因表达的基于组蛋白的表观遗传修饰如何 防止VCID中的内存丢失。总的来说，我们的调查将提供有效的机制见解， 以及正在进行的VCID远程调节的临床试验，VCID是我们RHC治疗的翻译对应物， 涉及用血压袖带装置诱导骨骼肌缺氧的重复循环。他们会 为推进流行病学和表观遗传学研究计划播下种子， 对VCID的诱导恢复力在人类中也可能是可遗传的。

PROJECT SUMMARY Neurocognitive impairment secondary to vascular contributions to cognitive impairment and dementia (VCID) exacts devastating tolls on our aging population, and to date, efficacious therapies remain elusive. Epigenetics- based therapeutics hold promise in this regard, as growing evidence continues to document the epigenetic induction of beneficial, disease-resilient phenotypes in response to distinct patterns of “positive stress” (`eustress'). Such profound findings indicate that reprogramming the activation and repression of a broad array of innate genes can actually protect the brain from injury in the absence of any exogenous, pharmacologic treatment. Indeed, recent findings from our lab using a well-established model of VCID indicate that repetitively conditioning mice with brief periods of nonharmful systemic hypoxia (RHC) prevents memory loss in vivo, and preserves hippocampal synaptic plasticity ex vivo, caused by three months of chronic cerebral hypoperfusion secondary to bilateral carotid artery stenosis. Moreover, we have discovered that adult, first-generation progeny of mice that were treated with RHC prior to mating also exhibit these same VCID-resilient phenotypes – in the absence of any direct treatment. Thus, the present proposal is founded on the overall hypothesis that adaptive epigenetics-based treatments can prevent VCID-associated cognitive loss, both within and across generations. Studies in Aim 1 are designed to determine if the aforementioned intergenerational protection against cognitive impairment that results from parental RHC requires treatment of both parents, or only the father or mother. The outcome of these studies will inform future studies of germ cell epigenetic change that ultimately underlies this transfer of induced, beneficial phenotypes. Studies in Aim 2 are designed to start unraveling the epigenetic regulatory mechanisms responsible for the protection against VCID-associated cognitive impairment in mice directly treated with RHC, focusing specifically on histone deacetylase 3 (HDAC3) and the role it plays in the transcriptional regulation of genes that contribute to RHC-mediated dementia resilience. Results of these studies will begin to build a molecular framework for how histone-based epigenetic modifications of gene expression can prevent memory loss in VCID. Overall, our investigations will provide mechanistic insights into the efficacious and ongoing clinical trials of remote conditioning for VCID, a translational counterpart of our RHC therapy that involves inducing repetitive cycles of skeletal muscle hypoxia with blood pressure cuff devices. And they will plant the seeds for advancing epidemiological and epigenetic research programs to explore the exciting possibility that an induced resilience to VCID may be heritable in humans as well.