Apoptotic Regulation and Neuroinflammation in Alzheimer's Disease

阿尔茨海默病的细胞凋亡调节和神经炎症

• 批准号: 10463986
• 负责人: Zintis Inde
• 金额: $ 6.76万
• 依托单位: HARVARD SCHOOL OF PUBLIC HEALTH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10463986
• 关键词: Adult; Advisory Committees; Affect; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease patient; American; Amyloid beta-Protein; Apoptosis; Apoptotic; Area; Automobile Driving; Autopsy; BAX gene; BCL2 gene; Bax protein; Bioinformatics; Biological Assay; Brain; CASP3 gene; Caregivers; Caspase; Cell Death; Cells; Characteristics; Competence; Dementia; Deposition; Development; Disease; Disease Progression; Down-Regulation; Educational process of instructing; Elderly; Ensure; Environment; Fellowship; Goals; Health system; Human; Inflammation; Inflammatory; Inflammatory Response; Interferon Type I; Intervention; Investigation; Knowledge; Laboratories; Laboratory Research; Laboratory Study; Lead; Link; Longevity; Measurement; Measures; Mediating; Memory Loss; Mentors; Methodology; Methods; Mitochondria; Mitochondrial DNA; Molecular; Mus; Mutation; Nerve Degeneration; Neurofibrillary Tangles; Neurons; Outer Mitochondrial Membrane; Pathogenesis; Pathologic; Pathway interactions; Patients; Pattern; Phenotype; Prevalence; Protein Family; Proteins; Public Health; Public Health Schools; Regulation; Research; Research Training; Resources; Role; Senile Plaques; Signal Pathway; Signal Transduction; Stereotyping; Stimulator of Interferon Genes; Stress; Symptoms; Testing; Therapeutic; Therapeutic Intervention; Time; Tissues; Training; Up-Regulation; Work; abeta accumulation; aged; aging brain; brain tissue; career development; cell type; design; experimental study; extracellular; faculty support; familial Alzheimer disease; human old age (65+); immunogenic; immunogenic cell death; improved; induced pluripotent stem cell; insight; neuroinflammation; neuron loss; normal aging; novel therapeutic intervention; prevent; protein activation; response; success; tau Proteins; therapeutically effective; training opportunity

Project Summary In patients with Alzheimer’s disease (AD), the progressive loss of neurons over time leads to memory loss and other devastating symptoms. Neuronal loss and inflammation in AD are strongly correlated with advanced age, but it remains unknown how age contributes to neuronal cell death or how cell death and neuroinflammation might be linked. This knowledge gap exists in part because previous studies of apoptosis, the canonical regulated cell death pathway, have A) lacked a functional assay to measure the apoptotic sensitivity of cells in the brain and B) relied on readouts of apoptosis that may not be present in neurons or other AD-affected cell types. The goal of my research is to better understand the regulation of apoptosis in the aging brain, investigating the links between aging, AD, inflammation, and apoptosis. Specifically, I propose to use BH3 and caspase profiling (BCP), a functional measurement of apoptotic sensitivity, and other methods to investigate the hypothesis that increased initiation of apoptosis in aging and AD promotes cell death and inflammation in neurons lacking apoptotic caspases. In Aim 1, I will quantify apoptotic priming, caspase activity, and inflammatory signaling in aged mice, measuring changes in each over lifespan and testing the role of the BCL-2 family protein BAX in these changes. In Aim 2, I will investigate these phenomena in human induced pluripotent stem cells (iPSCs), testing the effects of familial AD mutations and modulation of the cGAS/STING signaling pathway. In Aim 3, I will use BCP and other methods to study apoptotic priming and caspase competence in rapid autopsy human brain tissue, investigating potential differences in initiation and execution of apoptosis in neural cells between AD patients and healthy donor controls. The completion of these three aims will generate important new insights into the regulation of apoptosis in aging and AD, potentially revealing new opportunities for therapeutic intervention. The training plan for the proposed fellowship is designed to prepare me to lead my own research laboratory studying cell death in aging and neurodegeneration. This plan includes career development and training in laboratory methodologies, subject matter expertise, bioinformatic analysis, and classroom teaching. These training opportunities are made possible by my selection of Dr. Kristopher Sarosiek and Dr. Mark Albers as mentors, allowing me to draw on their expertise in their respective fields of cell death and neurodegeneration. I have sought out additional guidance and support from the faculty comprising my Career Development Committee and Scientific Advisory Committee, forming a strong network of mentors and collaborators. The research and training environment of the Harvard School of Public Health provides an ideal setting for the proposed activities, and I will draw on all these resources to complete the research and training plans described herein.

项目概要 在阿尔茨海默病 (AD) 患者中，随着时间的推移，神经元逐渐丧失，导致记忆力丧失和 AD 中的其他破坏性症状与高龄密切相关。 但目前尚不清楚年龄如何导致神经元细胞死亡或细胞死亡和神经炎症 这种知识差距的存在可能部分是因为之前对细胞凋亡（规范调节）的研究。 细胞死亡途径，A）缺乏测量大脑细胞凋亡敏感性的功能测定 B) 依赖于细胞凋亡的读数，而细胞凋亡的读数可能不存在于神经元或其他受 AD 影响的细胞类型中。 我的研究目标是更好地了解衰老大脑中细胞凋亡的调节，调查其中的联系 具体来说，我建议使用 BH3 和 caspase 分析 (BCP)， 细胞凋亡敏感性的功能测量，以及其他方法来研究增加细胞凋亡的假设 衰老和 AD 中细胞凋亡的启动促进缺乏凋亡的神经元的细胞死亡和炎症 在目标 1 中，我将量化老年小鼠的细胞凋亡启动、半胱天冬酶活性和炎症信号传导， 测量每个生命周期的变化并测试 BCL-2 家族蛋白 BAX 在这些变化中的作用。 在目标 2 中，我将研究人类诱导多能干细胞 (iPSC) 中的这些现象，测试效果 家族性 AD 突变和 cGAS/STING 信号通路的调节 在目标 3 中，我将使用 BCP 和 在快速尸检人脑组织中研究细胞凋亡启动和半胱天冬酶能力的其他方法， 研究 AD 患者神经细胞凋亡启动和执行的潜在差异 这三个目标的完成将为我们带来重要的新见解。 衰老和 AD 中细胞凋亡的调节，可能揭示治疗干预的新机会。 拟议奖学金的培训计划旨在帮助我做好领导自己的研究实验室的准备 研究衰老和神经退行性疾病中的细胞死亡该计划包括职业发展和培训。 实验室方法、主题专业知识、生物信息分析和课堂教学。 我选择 Kristopher Sarosiek 博士和 Mark Albers 博士作为培训机会 导师，让我能够利用他们在各自的细胞死亡和神经变性领域的专业知识。 已向我的职业发展委员会组成的教师寻求额外的指导和支持 和科学咨询委员会，形成强大的导师和合作者网络。 哈佛大学公共卫生学院的培训环境为拟议的活动提供了理想的环境， 我将利用所有这些资源来完成本文所述的研究和培训计划。