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.

项目摘要对认知障碍和痴呆的血管贡献继发的神经认知障碍（VCID）确切的毁灭性损失了我们的老龄化人口，迄今为止，有效的疗法仍然难以捉摸。表观遗传学 - 基于这一方面的理论有望，因为越来越多的证据继续记录了表观遗传学诱导有益的，疾病的表型，以响应“正应激”的不同模式（“ eustress”）。如此深刻的发现表明，重新编程了广泛阵列的激活和反射天生基因实际上可以保护大脑免受任何外源性药理的影响治疗。确实，我们实验室的最新发现使用了一个公认的VCID模型，表明重复性地短暂的无刺系统缺氧（RHC）的调节小鼠可防止体内记忆丧失，并且保存由三个月慢性脑部灌注引起的海马突触可塑性离体外继发于双侧颈动脉狭窄。此外，我们发现成人第一代的进步在交配之前用RHC处理的小鼠也表现出这些相同的VCID弹性表型 - 在没有任何直接治疗。这是根据自适应的总体假设建立的。基于表观遗传学的治疗可以防止在世代代内和几代人的内部和几代人的认知损失。 AIM 1中的研究旨在确定对认知的理性际际保护是否存在父母RHC造成的损害需要对父母或父亲或母亲的治疗。这些研究的结果将为未来对生殖细胞表观遗传变化的研究提供信息，这最终是基础的诱导的有益表型的转移。 AIM 2中的研究旨在开始阐明表观遗传负责保护小鼠与VCID相关认知障碍的调节机制直接用RHC处理，专门针对组蛋白脱乙酰基酶3（HDAC3）及其在对RHC介导的痴呆恢复能力的基因的转录调节。这些研究的结果将开始建立一个分子框架，用于基因表达的基于Hisstone的表观遗传修饰防止VCID的记忆丧失。总体而言，我们的调查将提供对高效的机械见解以及正在进行的远程调节临床试验VCID，这是我们RHC疗法的翻译对应物涉及引起血压袖口装置的骨骼肌缺氧的重复循环。他们会的种植种子，以推进流行病学和表观遗传学研究计划，以探索令人兴奋的诱发对VCID的韧性的可能性也可能在人类中是可遗传的。