Mechanisms underlying a decline in neural stem cell migration during aging

衰老过程中神经干细胞迁移下降的机制

• 批准号: 10750482
• 负责人: Olivia Yu Zhou
• 金额: $ 4.02万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-15 至 2026-12-14
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10750482
• 关键词: Adhesions; Adhesives; Adult; Affect; Age; Aging; Alzheimer' s Disease; Area; Automobile Driving; Biological Assay; Brain; Brain Diseases; Brain Injuries; Brain region; Candidate Disease Gene; Cell Adhesion; Cell physiology; Cells; Cellular biology; Chromatin; Clinical; Clustered Regularly Interspaced Short Palindromic Repeats; Coupled; Data; Data Analyses; Data Set; Defect; Development; Disease; Distal; Future; Genes; Genetic; Genetic Transcription; Genomics; Goals; Hippocampus; Impaired cognition; In Vitro; Individual; Injury; Intervention; Mentors; Molecular; Mus; Neurodegenerative Disorders; Neurology; Neurons; Nucleic Acid Regulatory Sequences; Pathway interactions; Patients; Phenotype; Physicians; Play; Process; Proliferating; Protein Kinase; Proteins; Regulation; Risk Factors; Role; Scientist; Signal Pathway; Site; Stroke; Testing; Therapeutic; Training; Traumatic Brain Injury; Up-Regulation; Work; age related; aging brain; brain repair; candidate identification; career; cell motility; cell type; cognitive function; effective therapy; experimental study; genetic manipulation; genome-wide; improved; in vivo; injury and repair; injury recovery; insight; interest; migration; mouse model; nerve stem cell; nervous system disorder; neuroblast; neurogenesis; neuromechanism; new therapeutic target; olfactory bulb; post stroke; protein kinase inhibitor; regeneration potential; repaired; rho; skills; small molecule; stem cell aging; stem cell biology; stem cell function; stem cell migration; stem cell niche; stroke model; stroke recovery; subventricular zone; therapeutic target; transcriptomics; Adhesions; Adhesives; Adult; Affect; Age; Aging; Alzheimer' s Disease; Area; Automobile Driving; Biological Assay; Brain; Brain Diseases; Brain Injuries; Brain region; Candidate Disease Gene; Cell Adhesion; Cell physiology; Cells; Cellular biology; Chromatin; Clinical; Clustered Regularly Interspaced Short Palindromic Repeats; Coupled; Data; Data Analyses; Data Set; Defect; Development; Disease; Distal; Future; Genes; Genetic; Genetic Transcription; Genomics; Goals; Hippocampus; Impaired cognition; In Vitro; Individual; Injury; Intervention; Mentors; Molecular; Mus; Neurodegenerative Disorders; Neurology; Neurons; Nucleic Acid Regulatory Sequences; Pathway interactions; Patients; Phenotype; Physicians; Play; Process; Proliferating; Protein Kinase; Proteins; Regulation; Risk Factors; Role; Scientist; Signal Pathway; Site; Stroke; Testing; Therapeutic; Training; Traumatic Brain Injury; Up-Regulation; Work; age related; aging brain; brain repair; candidate identification; career; cell motility; cell type; cognitive function; effective therapy; experimental study; genetic manipulation; genome-wide; improved; in vivo; injury and repair; injury recovery; insight; interest; migration; mouse model; nerve stem cell; nervous system disorder; neuroblast; neurogenesis; neuromechanism; new therapeutic target; olfactory bulb; post stroke; protein kinase inhibitor; regeneration potential; repaired; rho; skills; small molecule; stem cell aging; stem cell biology; stem cell function; stem cell migration; stem cell niche; stroke model; stroke recovery; subventricular zone; therapeutic target; transcriptomics

PROJECT SUMMARY Aging is the main risk factor for a variety of brain diseases, such as stroke and neurodegenerative diseases. Additionally, recovery from stroke and other types of brain injury declines with age. There is an unmet need for the development of more effective therapies centered on aging to counter the decline in repair capacity and the onset of neurodegenerative diseases. The adult brain contains neurogenic stem cell niches that have the potential to generate new progeny that migrate to distal sites, which could play a critical role for repair in age- related disease and injury. During aging, neural stem cells show a progressive loss in their ability to proliferate and give rise to new neurons (neurogenesis), and this is accompanied with a decline in repair ability. However, the mechanisms underlying this deficit are not well understood. My preliminary findings suggest that aging leads to changes in cell migration and adhesion abilities in neural stem cells, with activated neural stem cells and their progeny becoming less migratory with age. Based on these findings, my specific hypothesis is that with age, activated neural stem cells undergo reversible changes in cell migration and adhesion that lead to decreased neurogenesis. My proposal aims to elucidate the mechanisms underlying the age-related decline in migration in activated neural stem cells and uncover therapeutic strategies to mitigate this. Aim 1 will identify specific genes and regulatory factors that underlie the migratory defect in old activated neural stem cells and perturb them to boost the migration of old cells. Aim 2 will evaluate the therapeutic potential of blocking a signaling pathway that is important for regulation of cell migration and adhesion for repair upon stroke injury and explore the mechanisms by which it does so. Together, these independent aims will contribute to the field by giving a mechanistic understanding of how age causes a decline in neural stem cell function through dysregulation in cell migration and adhesion as well as provide a potential therapeutic avenue for improving neurogenesis and recovery from stroke in old brains. Through this work, I will be trained in the field of aging and neural stem cells as well as gain diverse expertise in cutting-edge experimental approaches. My scientific training coupled with mentoring by physician-scientists will help me in building a career as a physician-scientist interested in brain aging and treating patients with neurological diseases.

项目摘要 衰老是各种脑部疾病的主要危险因素，例如中风和神经退行性疾病。 此外，从中风和其他类型的脑损伤中恢复随着年龄的增长而下降。有未满足的需求 开发更有效的疗法以衰老为中心，以应对维修能力下降和 神经退行性疾病的发作。成年大脑包含具有神经源性干细胞壁ch 产生新后代的潜力，该后代迁移到远端地点，这对于年龄的维修起着至关重要的作用。 相关疾病和伤害。在衰老期间，神经干细胞的增殖能力逐渐丧失 并引起新的神经元（神经发生），这伴随着修复能力的下降。然而， 这种赤字的基础机制尚不清楚。我的初步发现表明衰老 导致细胞迁移和神经干细胞的粘附能力的变化，并具有活化的神经干细胞 他们的后代随着年龄的增长而变得越来越少。基于这些发现，我的具体假设是 随着年龄的增长，激活的神经干细胞会经历细胞迁移和粘附的可逆变化，导致 神经发生降低。我的建议旨在阐明与年龄相关下降的机制 激活的神经干细胞中的迁移并发现治疗策略以减轻这种情况。 AIM 1将识别特定的基因和调节因素，这些因素是旧激活中迁移缺陷的基础 神经干细胞并扰动它们以增强旧细胞的迁移。 AIM 2将评估阻断信号通路的治疗潜力，这对于调节很重要 中风损伤时的细胞迁移和粘附以修复并探索这样做的机制。 这些独立的目标将通过对年龄的方式给予机械理解，从而为该领域做出贡献 通过细胞迁移和粘附的失调以及 提供了一种潜在的治疗途径，可改善旧大脑中风的神经发生和恢复。 通过这项工作，我将在衰老和神经干细胞领域接受培训，并获得多种专业知识 在尖端的实验方法中。我的科学培训以及医师科学家的指导 将帮助我建立职业，成为对大脑衰老感兴趣的医生科学家，并治疗患者 神经疾病。