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

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.

项目概要 衰老是多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，中风和其他类型脑损伤的恢复随着年龄的增长而下降。有一个未满足的需求 开发以衰老为中心的更有效疗法，以应对修复能力的下降和 神经退行性疾病的发作。成人大脑含有神经源性干细胞生态位，其具有 产生迁移到远端位点的新后代的潜力，这可能在年龄修复中发挥关键作用 相关疾病和损伤。在衰老过程中，神经干细胞的增殖能力逐渐丧失 并产生新的神经元（神经发生），这伴随着修复能力的下降。然而， 这种缺陷背后的机制尚不清楚。我的初步研究结果表明，衰老 导致神经干细胞的细胞迁移和粘附能力发生变化，激活神经干细胞 随着年龄的增长，它们的后代的迁徙能力也随之减弱。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，从而导致 神经发生减少。我的建议旨在阐明与年龄相关的下降的潜在机制 激活的神经干细胞的迁移并揭示缓解这种情况的治疗策略。 目标 1 将识别导致旧激活细胞迁移缺陷的特定基因和调节因子。 神经干细胞并扰乱它们以促进老细胞的迁移。 目标 2 将评估阻断信号通路的治疗潜力，该信号通路对于调节 细胞迁移和粘附以修复中风损伤，并探讨其修复机制。 总之，这些独立的目标将通过机械地理解年龄如何变化来为该领域做出贡献。 通过细胞迁移和粘附的失调导致神经干细胞功能下降 为改善老年大脑的神经发生和中风恢复提供潜在的治疗途径。 通过这项工作，我将接受衰老和神经干细胞领域的培训，并获得多样化的专业知识 采用尖端的实验方法。我的科学训练加上医师科学家的指导 将帮助我成为一名对大脑衰老和治疗患有脑衰老的患者感兴趣的医师科学家 神经系统疾病。