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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