权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Epigenetic mechanisms of stress and age-related cognitive decline

压力和年龄相关认知能力下降的表观遗传机制

基本信息

批准号：
10627741
负责人：
Joseph Aloysius McQuail
金额：
$ 12.23万
依托单位：
UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10627741
关键词：
Acceleration Adrenal Glands Affect Age Age-associated memory impairment Aging Alzheimer&apos s Disease American Award Behavioral Bioinformatics Brain Brain region Censuses Chronic stress Clinical Clustered Regularly Interspaced Short Palindromic Repeats Cognitive Collaborations Competence DNA Methylation DNA Structure Data Dependence Elderly Epigenetic Process Equilibrium Exposure to Female Foundations Functional disorder Funding Gene Expression Genes Genetic Transcription Glucocorticoid Receptor Glucocorticoids Glutamates Goals Hippocampus Hypothalamic dysfunction Hypothalamic structure Impaired cognition Impairment Individual Interneurons Intervention Knowledge Laboratories Link Longevity Medial Mediating Mediator Memory Memory Loss Memory impairment Mentored Research Scientist Development Award Mentorship Mineralocorticoid Receptor Modeling Modification Molecular Morphology N-Methyl-D-Aspartate Receptors Neurobiology Neurons Neurophysiology - biologic function Neurosecretory Systems Physiological Pituitary Gland Predisposition Prefrontal Cortex Productivity Proteins Publishing Rattus Research Research Project Grants Severities Sex Differences Short-Term Memory Signal Transduction Site Stress Stressful Event Synapses Techniques Technology Temporal Lobe Testing Training Translating United States National Institutes of Health Viral Vector Work age related age related neurodegeneration aging brain base career design experience experimental study frontal lobe hippocampal pyramidal neuron human old age (65+)hypothalamic-pituitary-adrenal axis improved mRNA Expression male neural neural circuit neurotransmission novel novel therapeutic intervention prevent programs receptor response skills social synaptic function therapeutic development young adult

项目摘要

Project Summary/Abstract. Dysfunction of the hypothalamic-pituitary-adrenal axis, the major neuroendocrine system regulating physiological responses to stress, is a common feature of older individuals with memory loss, including those with Alzheimer’s disease. Indeed, accumulating effects of stress and glucocorticoid exposure across the lifespan are presumed to contribute to age-related memory loss and enhance susceptibility to Alzheimer’s disease via deleterious signaling alterations in glucocorticoid receptor-expressing neurons residing in the medial temporal and frontal lobes that support normal memory. Neural activity in the hippocampus, which supports declarative memory, or the prefrontal cortex, a region that is indispensable for working memory, requires a fine balance between persistent excitation of glutamatergic, pyramidal neurons and competitive inhibition provided by GABAergic interneurons. Recently published and preliminary findings from our laboratory indicate that memory loss observed in aging or following chronic stress is mechanistically linked to altered signaling via ionotropic NMDA receptors and metabotropic GABAB receptors in these brain regions. These similarities suggest a common mechanism contributes to memory loss in chronic stress and aging and, by extension, stress may interact with aging to increase severity of memory loss and susceptibility to age-related neurodegenerative disease. Our long-term goal is to understand the molecular mechanisms that translate stressful experiences into lasting changes in neural function that contribute to memory loss across the full lifespan and, in so doing, identify new targets that will lead to the development of therapeutics that protect or restore memory in older individuals. This project will use a rat model of age-related memory loss to test the hypotheses that 1) stress increases vulnerability to memory loss across the lifespan via DNA methylation that durably modifies transcriptional activity of genes that encode for synaptic proteins and 2) that stress-dependent molecular changes in the aged brain require signaling transduced by glucocorticoid and mineralocorticoid receptors. Such findings would be significant because they will identify specific molecular bases that transform experiential and physiological factors into impaired synaptic function and memory loss in later life and also establish a critical foundation for developing new therapeutic approaches to both prevent and reverse age- related memory loss. This proposal builds on the applicant’s long-standing scientific commitment to investigate the neural basis for cognitive decline in aging and Alzheimer’s disease. Productive collaborations initiated in a prior F32 award will be advanced and combined with new mentorship, affording significant technical and conceptual training in cutting-edge molecular approaches and bioinformatics. The scientific knowledge, technical competence, professional skills and original data cultivated under this K01 award will directly support the applicant’s transition to an independent scientific career as a PI leading his own NIH-funded research program.

项目总结/抽象。主要神经内分泌的下丘脑-垂体-肾上腺轴功能障碍