Microglial lysosomes and selective neuronal vulnerability

小胶质细胞溶酶体和选择性神经元脆弱性

• 批准号: 10829767
• 负责人: Lindsay Mitchell De Biase
• 金额: $ 4.99万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10829767
• 关键词: Age; Age-associated memory impairment; Aging; Behavior; Behavioral; Brain; Career Mobility; Cognitive; Complex; Confocal Microscopy; Doctor of Philosophy; Genes; Genotype; Goals; Grant; Image Analysis; Immune; Immunohistochemistry; International; Learning; Longevity; Lysosomes; Manuscripts; Maps; Memory; Mentors; Microglia; Mus; Neurobiology; Neurons; Outcome; Parents; Persons; Phenotype; Physicians; Postbaccalaureate; Postdoctoral Fellow; Preparation; Process; Research; Resolution; Rewards; Running; Scientist; Shapes; Specificity; Substantia nigra structure; Synapses; Training; Ventral Tegmental Area; Wild Type Mouse; Work; Writing; aging brain; brain cell; career development; cognitive function; cohort; confocal imaging; genetic manipulation; improved; middle age; neuronal circuitry; neuronal excitability; pars compacta; programs; response; skills; symposium; undergraduate student; young adult

Project Summary Microglial responses to aging are associated with substantive rearrangements in lysosome abundance, size, subcellular localization, as well as changes in the expression of numerous genes associated with lysosome function. Our group has recently shown that these microglial aging phenotypes emerge with pronounced regional specificity, with the ventral tegmental area (VTA) and substantia nigra pars compacta (SNc) microglia showing these changes by early middle age. With support from our parent R01, we are working to determine how these changes in microglial lysosome networks shape synapse-relevant microglial attributes and impact synapse integrity and neuronal excitability, which have been shown to be robust contributors to age-associated cognitive decline. The goal of the current diversity supplement is to support the career advancement of Ms Abigail Gutierrez through postbaccalaureate training and research aimed at directly probing relationships between microglial lysosome status and cognitive function in aging mice. During her undergraduate training at UCLA, Ms Gutierrez worked together with a postdoctoral fellow to develop a reward-based foraging task and showed that this task is sensitive to subtle changes in reward-based memory in late middle age, wild-type mice. Continued postbaccalaureate training in the lab will allow Ms Gutierrez to expand her scientific and professional skills in critical ways toward her goal of entering an MD/PhD program and becoming an independent physician-scientist. Abigail will gain essential skills in immunostaining, high resolution confocal microscopy and image analysis by carrying out immunohistochemistry to analyze microglial lysosomes in behaviorally-characterized young adult and aging mice. She will learn mouse husbandry, genotyping, and will further expand her skills in mouse behavior by running cohorts of mice with genetic manipulations of microglial lysosome status through the reward-based foraging task. Abigail will improve her independence, writing, and presentation skills through in-person and online classes, assisting with manuscript preparation, and sharing her research at international conferences. We have assembled an excellent mentoring team and mapped out milestones that render this period of postbaccalaureate training similar to a degree-granting masters program. This proposal will advance the career of an exceptional young scientist and allow her to show whether aging associated rearrangements in VTA and SNC microglial lysosomes represent a vulnerability in the aging brain, or a more adaptive response that helps sustain neuronal circuits and cognitive function later in the lifespan.

项目概要 小胶质细胞对衰老的反应与溶酶体的实质性重排有关 丰度、大小、亚细胞定位以及众多表达的变化 与溶酶体功能相关的基因。我们的小组最近表明这些小胶质细胞 衰老表型具有明显的区域特异性，腹侧被盖区 (VTA) 和黑质致密部 (SNc) 小胶质细胞在早期就显示出这些变化 中年。在母公司 R01 的支持下，我们正在努力确定这些变化如何 在小胶质细胞溶酶体网络中塑造突触相关的小胶质细胞属性和影响 突触完整性和神经元兴奋性，已被证明是强有力的贡献者 与年龄相关的认知能力下降。当前多样性补充的目标是支持 Abigail Gutierrez 女士通过学士后培训和研究实现职业发展 旨在直接探讨小胶质细胞溶酶体状态与认知之间的关系 在衰老小鼠中发挥作用。古铁雷斯女士在加州大学洛杉矶分校接受本科培训期间，曾工作 与博士后研究员一起开发了基于奖励的觅食任务，并表明 这项任务对中年晚期基于奖励的记忆的微妙变化很敏感，野生型 老鼠。继续在实验室进行学士学位后培训将使古铁雷斯女士能够扩展她的能力 科学和专业技能对她进入医学博士/博士课程的目标至关重要 并成为一名独立的医师科学家。阿比盖尔将获得以下方面的基本技能 免疫染色、高分辨率共聚焦显微镜和图像分析 免疫组织化学分析具有行为特征的年轻人的小胶质细胞溶酶体 成年和老年小鼠。她将学习小鼠饲养、基因分型，并将进一步拓展她的研究领域。 通过对小鼠进行小胶质细胞基因操作，研究小鼠行为技能 通过基于奖励的觅食任务来确定溶酶体的状态。阿比盖尔将提高她的独立性， 通过面对面和在线课程的写作和演示技巧，协助手稿 准备工作，并在国际会议上分享她的研究成果。我们组装了一个 优秀的指导团队并制定了里程碑，使这一时期 类似于授予学位的硕士学位课程的学士后培训。该提案将 促进一位杰出的年轻科学家的职业生涯，让她证明衰老是否 VTA 和 SNC 小胶质细胞溶酶体中的相关重排代表了 老化的大脑，或更适应性的反应，有助于维持神经元回路和认知 在生命周期的后期发挥作用。