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Regulation of adult hippocampal function by the neural stem and progenitor cell secretome

神经干和祖细胞分泌组对成人海马功能的调节

基本信息

批准号：
10543548
负责人：
Elizabeth Diana Kirby
金额：
$ 38.94万
依托单位：
OHIO STATE 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：
2021-12-23 至 2026-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10543548
关键词：
Acute Adult Affect Amino Acids Astrocytes Behavioral Brain Brain Diseases Brain Injuries Brain region Cells Cognitive Collection Coupled Cytoplasmic Granules Data Dimensions Disease Emotions Exposure to Functional disorder Gatekeeping Genetic Code Goals Growth Factor Health Hippocampus Homeostasis Impairment Individual Influentials Injury Literature Longevity Mammals Mediating Memory Modeling Natural regeneration Neurons Neurophysiology - biologic function Parahippocampal Gyrus Pattern Physiology Population Process Production Protein Isoforms Protein Secretion Proteins Recovery Regulation Reporting Research Role Shapes Signal Transduction Source Testing Therapeutic Time Tissues Transgenic Organisms Undifferentiated Vascular Endothelial Growth Factors Work adult neurogenesis autocrine behavioral response brain health cell type cytokine dentate gyrus emotion regulation emotional functioning excitotoxicity experimental study functional improvement indexing insight knock-down nerve stem cell neural neurogenesis paracrine pleiotropism progenitor response to injury source localization stem stem cell proliferation stem cells tissue regeneration viral rescue

项目摘要

A unique neurogenic niche in the adult hippocampus hosts neural-lineage stem cells that can persist throughout the lifespan in a wide range of adult mammals. Uncovering the functional role of these stem cells and how they interact with other cell types in the niche can provide insight in to the mechanisms that mediate hippocampal cognitive-emotional functions, as well as potential mechanisms for regenerating tissue in the adult brain. Recently, stem cell secreted proteins (i.e. the stem cell secretome) have emerged as influential players in tissue homeostasis. However, relatively little is known about either the content or the function of the secretome of endogenous neural stem cells and their progenitors (NSPCs) in the adult hippocampus. Our preliminary data reveal that adult hippocampal NSPCs may regulate their microenvironment through the production of the soluble protein, vascular endothelial growth factor (VEGF). We find that NSPCs synthesize large quantities of VEGF in their hippocampal niche and that NSPC-derived VEGF is necessary for sustaining healthy hippocampal function. We propose to investigate the hypothesis that NSPCs support hippocampal function by direct actions of VEGF that suppress neuronal hyperexcitability, ultimately supporting memory function, as well as protecting it from injury. In Aim 1, we will use RNAsequencing as well as genetic code expansion coupled with biorthogonal non- canonical amino acid protein tagging to determine the specific local contributions of NSPCs to VEGF isoforms in the cell layers of the dentate gyrus subregion where these cells reside. In Aim 2, we will use transgenic knockdown and viral rescue models to investigate how dentate gyrus circuit activity is regulated specifically by NSPC-derived VEGF. In Aim 3, we will use transgenic knockdown and viral rescue models to determine how NSPC-VEGF influences hippocampal behavioral functions and vulnerability to excitotoxic injury. The completion of this work will establish a new functional dimension of endogenous NSPCs via their secretome, and advance understanding of how hippocampal health is actively maintained in a unique niche of the adult brain.

成体海马体中有一个独特的神经源性生态位，可容纳可持续存在的神经系干细胞