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.

项目总结