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：
10374129
负责人：
Joseph Aloysius McQuail
金额：
$ 11.93万
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/10374129
关键词：
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 (Brain)Hypothalamic dysfunction Hypothalamic structure Impaired cognition Impairment Individual Interneurons Intervention Knowledge Laboratories Lead Life Link Longevity Medial Mediating Mediator of activation protein 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 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 circuit neurotransmission novel novel therapeutic intervention prevent programs receptor relating to nervous system 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.

项目摘要/摘要：下丘脑-垂体-肾上腺轴功能障碍，主要神经内分泌。调节对压力的生理反应的系统，是记忆丧失的老年人的一个共同特征，事实上，压力和糖皮质激素暴露的影响不断累积。据推测，在整个生命周期中，这些因素都会导致与年龄相关的记忆丧失，并增加对阿尔茨海默氏病是通过表达糖皮质激素受体的神经元中的有害信号传导而引起的位于内侧颞叶和额叶，支持海马体的正常记忆。支持陈述性记忆或前额皮质，这是工作记忆不可或缺的区域，需要谷氨酸能、锥体神经元的持续兴奋和竞争性之间的良好平衡 GABA能中间神经元提供的抑制作用是我们实验室最近发表的初步研究结果。表明在衰老或慢性压力后观察到的记忆丧失与通过这些大脑区域中的离子型 NMDA 受体和代谢型 GABAB 受体进行信号传导。相似之处表明慢性压力和衰老导致的记忆丧失有一个共同的机制，延长，压力可能与衰老相互作用，增加记忆丧失的严重性和对与年龄相关的敏感性我们的长期目标是了解转化的分子机制。压力经历会转化为神经功能的持久变化，从而导致整个人的记忆丧失寿命，并在此过程中确定新的目标，从而开发出保护或保护的疗法恢复老年人的记忆该项目将使用与年龄相关的记忆丧失的大鼠模型来测试假设 1) 压力会通过 DNA 甲基化增加整个生命周期中记忆丧失的脆弱性持久地改变编码突触蛋白的基因的转录活性，2) 应激依赖性老年大脑的分子变化需要糖皮质激素和盐皮质激素转导的信号传导这些发现将具有重要意义，因为它们将识别转化的特定分子碱基。经验和生理因素会导致突触功能受损和晚年记忆丧失为开发预防和逆转衰老的新治疗方法奠定重要基础该提案建立在申请人对调查的长期科学承诺的基础上。衰老和阿尔茨海默病中认知能力下降的神经基础之前的 F32 奖项将得到提升，并与新的指导相结合，提供重要的技术和尖端分子方法和生物信息学的概念培训。此次K01奖培养的能力、专业技能和原始数据将直接支持申请人作为 PI 领导自己的 NIH 资助的研究项目，过渡到独立的科学职业。