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.

项目摘要 小胶质的对衰老的反应与溶酶体的实质重排有关 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 具有明显区域特异性出现的老化表型，腹侧对段区域 （VTA）和底底nigra pars commcacta（SNC）小胶质细胞显示这些变化。 中年。在父母R01的支持下，我们正在努力确定这些改变 在小胶质细胞中，溶酶体网络形成与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，已被证明是强大的贡献者 与年龄相关的认知下降。当前多样性补充的目的是支持 阿比盖尔·古铁雷斯女士的职业发展，通过后核后培训和研究 旨在直接探测小胶质溶酶体状态与认知之间的关系 衰老小鼠的功能。在加州大学洛杉矶分校的大学培训期间，古铁雷斯女士工作 与博士后研究员一起制定基于奖励的觅食任务，并表明 此任务对中年晚期基于奖励的记忆的细微变化敏感 老鼠。在实验室中继续进行后的后龙培训将使古铁雷斯女士能够扩大她 以关键的方式进行科学和专业技能，以实现她进入MD/PhD计划的目标 并成为独立的医师科学家。阿比盖尔将获得基本技能 通过进行免疫染色，高分辨率共聚焦显微镜和图像分析 免疫组织化学以分析行为特征的年轻人中的小胶质细胞溶酶体 成人和老化小鼠。她将学习老鼠饲养，基因分型，并将进一步扩大她 通过与小胶质细胞的遗传操纵的小鼠共同行为的技能 溶酶体状态通过基于奖励的觅食任务。阿比盖尔将改善她的独立性， 通过面对面和在线课程的写作和演讲技巧，协助手稿 准备，并在国际会议上分享她的研究。我们已经组装了 出色的指导团队并绘制了这一时期的里程碑 毕业后的培训类似于学位授予硕士课程。该提议将 促进一位杰出的年轻科学家的职业，并允许她展示是否衰老 VTA和SNC小胶质细胞溶酶体中的相关重排代表 衰老的大脑或更适应性的反应，有助于维持神经元电路和认知能力 在寿命后期的功能。