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

• 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
• 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

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.

成人海马中独特的神经源性小众构成神经linege干细胞，可以持续到整个过程中 在各种成年哺乳动物中的寿命。发现这些干细胞的功能作用以及它们如何 与利基市场中的其他细胞类型相互作用可以为介导海马的机制提供见解 认知情感功能以及成人大脑中再生组织的潜在机制。 最近，干细胞分泌的蛋白质（即干细胞分泌组）已成为组织中有影响力的参与者 稳态。但是，关于分泌的内容或功能相对较少 成年海马中的内源性神经干细胞及其祖细胞（NSPC）。我们的初步数据 揭示成年海马NSPC可以通过生产来调节其微环境 蛋白质，血管内皮生长因子（VEGF）。我们发现NSPC合成了大量的VEGF 他们的海马利基市场和NSPC衍生的VEGF对于维持健康的海马功能是必需的。 我们建议研究NSPC通过VEGF的直接作用支持海马功能的假设 抑制神经元过度兴奋性，最终支持记忆功能，并保护其免受 受伤。在AIM 1中，我们将使用rnasequencing以及遗传代码扩展以及生物息息非 - 规范氨基酸蛋白标记，以确定NSPC对VEGF同工型的特定局部贡献 在这些细胞居住的齿状回齿状区域的细胞层中。在AIM 2中，我们将使用转基因 敲低和病毒救援模型，以研究齿状回电路活性如何特别调节 NSPC衍生的VEGF。在AIM 3中，我们将使用转基因敲低和病毒救援模型来确定如何 NSPC-VEGF影响海马行为功能和兴奋性损伤的脆弱性。完成 这项工作将通过其分泌组来建立内源性NSPC的新功能维度，并促进 了解如何在成年大脑的独特利基市场中积极维持海马健康。