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Neuronal Circuit Maintenance in Healthy Aging

健康老龄化中的神经元回路维护

基本信息

批准号：
10762550
负责人：
Elizabeth A Pollina
金额：
$ 24.89万
依托单位：
WASHINGTON UNIVERSITY
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：
2021-02-01 至 2026-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10762550
关键词：
Acceleration Acetyltransferase Action Potentials Acute Adult Affect Age Aging Atrophic Binding Bioinformatics Brain Calcium Calcium Signaling Cell membrane Cell physiology Cellular Stress Cellular biology Chromatin Communication Complex Cues DNA Damage DNA Double Strand Break DNA Repair Data Data Set Defect Deterioration Diagnosis Disease Double Strand Break Repair Elements Enhancers Epidemiology Functional disorder Gamma-H2AX Gene Activation Gene Expression Gene Expression Profile Gene Expression Regulation Gene Targeting Genes Genetic Transcription Genome Stability Genomics Goals HTATIP gene Hippocampus Human Impaired cognition Impairment Incidence Individual Inhibitory Synapse Invertebrates Knockout Mice Knowledge Learning Link Longevity Maintenance Maps Mediating Mediator Memory Molecular Mus Mutation NPAS4 gene Nervous System Neurobiology Neurodegenerative Disorders Neurons Phase Population Predisposition Process Property Regulation Regulator Genes Repair Complex Reporting Risk Factors Role Signal Transduction Site Stimulus Synapses Testing Tissues Training Transcription Coactivator Transcriptional Regulation Work age related aging brain aging population cell type cognitive training design excitatory neuron experimental study gene induction genomic locus healthy aging in vivo inhibitory neuron juvenile animal neural circuit neurodegenerative dementia neuronal circuitry novel premature preservation programs promoter protein complex recruit repaired response sensory stimulus skills transcription factor

项目摘要

Project Summary The overarching goal of this study is to identify new mechanisms that preserve neuronal function with age. As the world's aging population steadily increases, the number of diagnoses for neurodegenerative disease and dementia is projected to more than double within the next 30 years, underscoring our immediate need to understand the cellular and molecular basis of brain aging. Atrophy of the connections that mediate neuronal communication leads to aberrant activity within neural circuits in the aging brain. How changes in activity modify the properties of aging neurons is not yet clear. The brain adapts to neuronal activity in part via the induction of new gene expression programs encoding critical cell-type-specific mediators of circuit plasticity. Whether re-engaging the regulators of these gene programs in aging brains can ameliorate declining neuronal function remains unknown. The bHLH-PAS transcription factor NPAS4 constitutes a major regulator of activity-dependent gene programs in both mice and humans. NPAS4 integrates into the NuA4/TIP60 acetyltransferase protein complex, a transcriptional co-activator and DNA repair complex, which has been linked to learning and memory in invertebrates. Intriguingly, activity-dependent elements targeted by NPAS4 transiently acquire a chromatin mark of DNA damage signaling upon neuronal activation (γH2AX), raising the possibility that NPAS4 may function at these sites to help repair damage resulting from activity-driven transcription. In preliminary data, I discovered that Npas4 knockout mice die prematurely with signs of cell stress in the hippocampus. This study will examine the hypothesis that the newly identified NPAS4:NuA4 complex has evolved a protective role to promote the sustained functionality of neurons by maintaining transcriptional control and genome stability at activity-dependent gene loci. I will examine age-dependent changes to Npas4 regulation and activity- dependent gene induction across neuronal cell types (Aim 1, K99) and identify critical gene targets of this complex in activated neurons (Aim 2, K99). During the R00 phase, I will expand upon these ideas to explore a novel role for this activity-dependent protein complex in the repair of directed DNA damage at enhancers and promoters, and will examine how this directed DNA repair activity changes with age (Aim 3, K99). In the long term, I will leverage the datasets, and new skills in bioinformatics and neurobiology acquired during the K99 training period, to identify new mechanisms and molecules that preserve cell-type-specific function in the nervous system. My ultimate goal is to design targeted strategies to slow or reverse decline in the neuronal subtypes most susceptible to age-dependent diseases.

项目总结