Microglial lysosomes and selective neuronal vulnerability

项目摘要 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、亚细胞定位以及许多基因表达的变化 与溶酶体功能相关的基因。我们的小组最近发现，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)小胶质细胞早期表现出这些变化 人到中年。在母公司R01的支持下，我们正在努力确定这些变化是如何 在小胶质细胞中，溶酶体网络形成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 与年龄相关的认知衰退。目前的多样性补充的目标是支持 阿比盖尔·古铁雷斯女士通过毕业后培训和研究获得职业发展 旨在直接探讨小胶质细胞溶酶体状态与认知之间的关系 对衰老小鼠的作用。在加州大学洛杉矶分校接受本科培训期间，古铁雷斯女士 与一位博士后一起开发了一项基于奖励的觅食任务，并表明 这项任务对中年后期基于奖励的记忆的细微变化很敏感，野生型 老鼠。继续在实验室接受学士学位后的培训将使古铁雷斯女士能够扩大她的 以关键的方式掌握科学和专业技能，以达到进入医学博士学位课程的目标 成为一名独立的内科医生兼科学家。阿比盖尔将获得基本技能 免疫染色、高分辨率共聚焦显微镜和图像分析 行为特征青少年小胶质细胞溶酶体的免疫组织化学分析 成年和衰老小鼠。她将学习老鼠饲养，基因分型，并将进一步扩大她的 通过小胶质细胞基因操作的小鼠队列运行小鼠行为的技巧 通过基于奖励的觅食任务获得溶酶体状态。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能，协助撰写手稿 准备工作，并在国际会议上分享她的研究成果。我们已经组装了一个 优秀的指导团队，并制定了里程碑，使这段时间 类似于授予学位的硕士课程的毕业后培训。这项提议将 推进一位杰出的年轻科学家的职业生涯，并让她展示出 VTA和SNC小胶质溶酶体的相关重排是一种脆弱性 老化的大脑，或帮助维持神经元回路和认知的更适应的反应 在以后的生命周期中起作用。

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.