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Investigating the role of astrocyte specific NFIA during initiation and progression of AD pathogenesis

研究星形胶质细胞特异性 NFIA 在 AD 发病机制的起始和进展过程中的作用

基本信息

批准号：
10722872
负责人：
Dongjoo Choi
金额：
$ 10.23万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-01 至 2028-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10722872
关键词：
Acceleration Adult Affect Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease model Alzheimer&apos s disease pathology Alzheimer&apos s disease patient Animal Model Astrocytes Behavior Behavioral Behavioral Assay Bioinformatics Biology Brain Brain Injuries Brain region Calcium Calcium Signaling ChIP-seq Coupled Data Development Disease Disease Progression Electrophysiology (science)Genes Genetic Genetic Transcription Glial Fibrillary Acidic Protein Goals Health Hippocampus Human Ion Channel Journals Knowledge Learning Link Mediating Medicine Memory Mentors Methods Molecular Multiple Sclerosis Mus NFIA gene Nerve Degeneration Neurodegenerative Disorders Neuroglia Neurons Neurotransmitters Pathogenesis Pathologic Pathway interactions Pattern Phagocytosis Phenotype Physiological Physiology Play Production Property Publishing Regulation Research Role Sampling Series Signal Transduction Testing Time Training Up-Regulation Viral candidate validation career development clinical investigation college experimental study gain of function gene network genetic manipulation glial cell development loss of function nervous system disorder neurotransmission novel strategies overexpression preservation response tool transcription factor transcriptome transcriptome sequencing

项目摘要

Project Summary / Abstract Astrocytes are the most abundant and diverse glial cells in the adult brain, comprising 70% of the glial constituency. Astrocytes perform essential tasks for normal brain function and contribute to various neurological disorders, including neurodegenerative diseases such as Alzheimer's disease (AD). However, their role in health and disease remains a mystery. Recently, we found that NFIA contributes to astrocyte-mediated regulation of brain circuits and memory in the brain, and it was highly increased in reactive astrocytes in the AD mouse brain. Although the reactive astrocytes are closely associated with degenerating neurons across multiple brain regions in patients with AD, it is largely unknown how astrocytes contribute to the initiation and progression of AD and how astrocytic NFIA regulates functions of astrocytes and reactive astrocytes. Here, using a newly generated animal model, in preliminary data, we found that gain or- / loss of- NFIA in astrocytes showed decreasing/increasing of A accumulation in AD mouse brain. These results lead us to the hypothesis that astrocytic NFIA has a role in astrocytes and reactive astrocytes for AD pathogenesis. To test this, we proposed experiments to confirm NFIA expression in the human AD brain and to analyze AD pathogenesis in AD mouse brain with behavioral alteration by time different NFIA manipulation in astrocytes (Aim 1). We next asked how NFIA contributes to the alteration of astrocyte function for AD pathogenesis since NFIA regulates astrocyte core properties. To test this, we proposed experiments to confirm alteration of A production / clearance ability of astrocytes, astrocytes calcium activation and astrocyte mediated neurotransmission by time different NFIA manipulation (Aim 2). Preliminary data revealed that NFIA regulated AD-related genes in hippocampal astrocytes. Therefore, we will use RNA-seq and ChIP-seq to investigate the NFIA-regulated candidates and networks for AD pathogenesis in astrocytes and reactive astrocytes. Furthermore, we will validate the candidates using gene manipulating methods in astrocytes and reactive astrocytes from the initiation to progression stages of AD pathogenesis (Aim 3). These results will reveal whether and how astrocytic NFIA contributes to AD pathogenesis and how astrocytes contribute to AD pathogenesis from initiation to progression. For my career development, these studies will provide training in the glia-AD relationship under my mentor Dr. Deneen (expert in astrocyte biology) and co-mentor Dr. Jankowsky (expert in Alzheimer's disease) at Baylor College of Medicine. Since astrocytes are intimately connected with neurons and are dysregulated in all neurological disorders, this proposal aims to uncover how astrocytes contribute to neurodegenerative disease development. Towards this goal, the proposed research will apply new approaches to astrocyte biology to delineate genetic and functional mechanisms involved in the progression of neurodegeneration.

项目摘要/摘要