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Reducing vascular cognitive impairment within and across generations by epigenetic conditioning

通过表观遗传调节减少代内和代际间的血管性认知障碍

基本信息

批准号：
10212499
负责人：
JEFFREY M GIDDAY
金额：
$ 40.43万
依托单位：
LSU HEALTH SCIENCES CENTER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-03-01 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10212499
关键词：
Acetylation Acute Adult Alzheimer&apos s Disease Animals Bilateral Biological Blood Pressure Brain Brain Injuries Carotid Stenosis Cerebral Ischemia Cholinesterase Inhibitors Chronic Clinical Trials DNA Data Deacetylation Dementia Devices Disease Enzymes Epidemiology Epigenetic Process Exhibits Fathers Future Gene Expression Gene Expression Regulation Gene-Modified Generations Genes Genetic Transcription Germ Cells Glaucoma HDAC3 gene Heritability Hippocampus (Brain)Histone Deacetylase Inhibitor Histones Human Hypoxia Impaired cognition Intention Intergenerational transfer Investigation Long-Term Potentiation Measures Mediating Memory Loss Messenger RNA Modeling Modification Molecular Mothers Mus Myocardial Ischemia Neurocognitive Neurocognitive Deficit Observational Study Organism Outcome Study Parents Partner in relationship Pattern Pharmacological Treatment Phenotype Plants Play Prefrontal Cortex Problem Solving Process Proteins Public Health Radial Repression Research Retinal Ganglion Cells Role Secondary to Seeds Short-Term Memory Side Skeletal Muscle Somatic Cell Stimulus Stress Stroke Synaptic plasticity Testing Therapeutic Thinking Tissues Transcriptional Regulation Vascular Cognitive Impairment acute stroke aging population arm base cell injury cerebral hypoperfusion chronic neurologic disease cognitive function cohort conditioning design diet and exercise disorder risk donepezil efficacious treatment epigenetic regulation executive function experience high reward high risk in vivo insight intergenerational memory recognition mouse model neurovascular non-genomic novel object recognition preclinical study preconditioning preservation prevent programs progressive neurodegeneration resilience response spatial memory stressor vascular cognitive impairment and dementia vascular risk factor

项目摘要

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.

项目概要血管导致认知障碍和痴呆 (VCID) 继发神经认知障碍给我们的老龄化人口带来了毁灭性的损失，迄今为止，有效的治疗方法仍然难以捉摸。表观遗传学- 基于治疗的方法在这方面有希望，因为越来越多的证据继续记录表观遗传针对不同模式的“积极压力”诱导有益的、抗病的表型（“良性压力”）。如此深刻的发现表明，重新编程一系列广泛的激活和抑制在没有任何外源性药物作用的情况下，先天基因实际上可以保护大脑免受损伤治疗。事实上，我们实验室最近使用完善的 VCID 模型得出的研究结果表明，重复对小鼠进行短暂无害的全身性缺氧（RHC）调节可以防止体内记忆丧失，并且保留由三个月慢性脑灌注不足引起的海马突触可塑性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接受 RHC 治疗的小鼠也表现出相同的 VCID 恢复表型 - 在没有任何直接治疗。因此，本提案建立在自适应的总体假设之上基于表观遗传学的治疗可以预防 VCID 相关的认知丧失，无论是在代内还是跨代。目标 1 的研究旨在确定上述针对认知的代际保护是否有效。父母 RHC 导致的损伤需要父母双方或仅父亲或母亲的治疗。这这些研究的结果将为未来对最终导致这一现象的生殖细胞表观遗传变化的研究提供信息诱导的有益表型的转移。目标 2 的研究旨在开始解开表观遗传学的谜团。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 (HDAC3) 及其在有助于 RHC 介导的痴呆恢复的基因的转录调控。这些研究的结果将开始建立一个分子框架，以了解基于组蛋白的基因表达表观遗传修饰如何能够防止 VCID 内存丢失。总的来说，我们的研究将为有效的机制提供机制上的见解。以及正在进行的 VCID 远程调理临床试验，这是我们的 RHC 疗法的转化对应物涉及使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项目播下种子，探索令人兴奋的对 VCID 的诱导恢复能力也可能在人类中遗传。