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.

项目摘要 衰老是多种脑部疾病的主要危险因素，如中风和神经退行性疾病。 此外，中风和其他类型的脑损伤的恢复随着年龄的增长而下降。的需求尚未得到满足 以衰老为中心的更有效疗法的发展，以对抗修复能力的下降， 神经退行性疾病的发病。成年人的大脑含有神经源性干细胞龛， 有可能产生迁移到远端位点的新后代，这可能在年龄的修复中发挥关键作用， 相关疾病和伤害。在衰老过程中，神经干细胞表现出增殖能力的逐渐丧失 并产生新的神经元（神经发生），同时伴有修复能力的下降。然而，在这方面， 造成这一缺陷的机制尚不清楚。我的初步发现表明 导致神经干细胞的细胞迁移和粘附能力发生变化， 它们的后代随着年龄的增长迁移性越来越小。根据这些发现，我的具体假设是， 随着年龄的增长，激活的神经干细胞在细胞迁移和粘附方面发生可逆的变化， 神经发生减少。我的建议旨在阐明与年龄相关的衰老的机制， 并发现缓解这种情况的治疗策略。 目的1将确定特定的基因和调节因素，在迁移缺陷的老年激活 神经干细胞并扰乱它们以促进老细胞的迁移。 目的2将评估阻断一个信号通路的治疗潜力，该信号通路对调节 细胞迁移和粘附对中风损伤后的修复，并探讨其机制。 总之，这些独立的目标将有助于该领域的机械理解如何年龄 通过细胞迁移和粘附的失调导致神经干细胞功能下降， 为改善老年脑卒中的神经发生和恢复提供了潜在的治疗途径。 通过这项工作，我将在衰老和神经干细胞领域接受培训，并获得各种专业知识 尖端的实验方法。我的科学训练加上医生科学家的指导 将帮助我建立一个职业生涯作为一个医生，科学家感兴趣的大脑老化和治疗病人 神经系统疾病