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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.

项目总结认知障碍和痴呆(VCID)继发于血管因素的神经认知障碍对我们老龄化的人口造成毁灭性的代价，到目前为止，有效的治疗方法仍然难以捉摸。表观遗传学- 基础疗法在这方面很有希望，因为越来越多的证据继续证明表观遗传学在不同的“积极应激”模式下诱导有益的、抗病的表型 (‘有压力的’)。如此深刻的发现表明，对广泛阵列的激活和抑制进行重新编程在没有任何外源、药理作用的情况下，先天基因实际上可以保护大脑免受损伤治疗。事实上，我们实验室使用一个成熟的VCID模型的最新发现表明，重复地小鼠处于短期无害的全身性缺氧(RHC)状态可防止体内记忆丧失，并且保留慢性脑低灌流三个月所致海马区突触的体外可塑性继发于双侧颈动脉狭窄。此外，我们还发现，成年的第一代后代在交配前接受RHC治疗的小鼠中，也表现出相同的VCID-弹性表型-在没有任何直接治疗。因此，本提案的基础是适应性的总体假设基于表观遗传学的治疗可以预防VCID相关的认知损失，无论是在几代人之内还是跨代人。目标1中的研究旨在确定上述针对认知障碍的代际保护由父母RHC引起的损害需要父母双方或仅父亲或母亲的治疗。这个这些研究的结果将为未来对生殖细胞表观遗传学变化的研究提供信息，最终奠定这一基础。诱导的、有益的表型转移。AIM 2的研究旨在开始解开表观遗传学保护VCID相关认知功能障碍的调节机制直接用RHC治疗，特别关注组蛋白脱乙酰酶3(HDAC3)及其在参与RHC介导的痴呆症恢复力的基因转录调控。这些研究的结果将开始建立一个分子框架，研究基于组蛋白的基因表达的表观遗传修饰如何防止VCID中的记忆丢失。总体而言，我们的调查将提供对有效的和正在进行的VCID远程调节的临床试验，VCID是我们的RHC疗法的翻译对应物，包括使用血压袖带装置诱导骨骼肌缺氧的重复循环。他们会的为推进流行病学和表观遗传学研究计划播下种子，探索令人兴奋的对VCID的诱导恢复力在人类中也可能是可遗传的。