Mechanisms underlying a decline in neural stem cell migration during aging

项目总结 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率随着年龄的增长而下降。有一种未得到满足的需求 以衰老为中心的更有效疗法的开发，以对抗修复能力的下降和 神经退行性疾病的发病。成人大脑中含有神经源性干细胞壁龛，它们具有 有可能产生迁移到远端部位的新后代，这可能对年龄的修复起关键作用- 相关疾病和伤害。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(神经再生)，这伴随着修复能力的下降。然而， 这种赤字背后的机制还没有得到很好的理解。我的初步发现表明，衰老 导致神经干细胞与激活的神经干细胞的细胞迁移和黏附能力的变化 随着年龄的增长，它们的后代变得不那么迁徙。基于这些发现，我的具体假设是 随着年龄的增长，激活的神经干细胞在细胞迁移和黏附方面经历了可逆的变化，导致 神经发生减少。我的建议旨在阐明与年龄相关的年龄相关性下降的机制 激活的神经干细胞的迁移，并发现缓解这种情况的治疗策略。 目标1将确定导致老年人活动性迁移缺陷的特定基因和调控因素 神经干细胞，并干扰它们以促进旧细胞的迁移。 目的2将评估阻断一条信号通路的治疗潜力，该通路对于调节 中风损伤后修复的细胞迁移和黏附，并探索其机制。 这些独立的目标加在一起，将通过提供对年龄的机械性理解来为该领域做出贡献 通过细胞迁移和黏附的失调导致神经干细胞功能的下降 为改善老年脑卒中的神经再生和康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，并获得不同的专业知识 在尖端的实验方法中。我的科学训练加上内科科学家的指导 将帮助我建立自己的职业生涯，成为一名对脑老化和治疗脑部疾病患者感兴趣的内科科学家 神经系统疾病。

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.