Senescent Vascular Cells as Mediators of Cognitive Decline

衰老血管细胞作为认知衰退的介质

• 批准号: 10282110
• 负责人: Marissa Joy Schafer
• 金额: $ 24.9万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10282110
• 关键词: AP20187; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease related dementia; Anxiety; Astrocytes; Blood Vessels; Brain; CCL2 gene; Caspase; Cell Aging; Cells; Cerebrovascular Disorders; Cerebrovascular system; Clinic; Cognition; Cognitive; Cognitive deficits; Dasatinib; Data; Dementia; Deterioration; Development; Elderly; Electron Microscopy; Endothelial Cells; Endothelium; Eotaxin; Excision; Fluorescence-Activated Cell Sorting; Foundations; Functional disorder; Genetic; Goals; Health; Homeostasis; Image; Immunofluorescence Immunologic; Impaired cognition; Impairment; In Vitro; Infiltration; Inflammation; Inflammatory; Ink; Intervention; Intuition; Knowledge; LOX gene; Leukocytes; Matrix Metalloproteinases; Measures; Mediating; Mediator of activation protein; Memory; Mentors; Methods; Microglia; Monitor; Mus; Neurons; Pathogenesis; Pericytes; Pharmaceutical Preparations; Pharmacology; Phase; Phenotype; Physiology; Population; Prevalence; Prevention; Publishing; Quercetin; Research; Research Personnel; Risk Factors; Role; Structure; Testing; Tight Junctions; Tissues; Training; Transgenic Mice; Transgenic Organisms; Vascular Diseases; Vasomotor; Work; age related; aged; aging brain; aging population; base; basilar artery; behavior test; beta-Galactosidase; blood-brain barrier permeabilization; career; career development; cell age; cell type; cerebral microvasculature; cerebrovascular; cognitive function; cognitive testing; executive function; experimental study; fisetin; healthspan; improved; in vivo; novel; novel strategies; programs; senescence; skills; treatment strategy

PROJECT SUMMARY The goals of this proposal are to (1) obtain experimental skills and career training necessary to develop an independent research program investigating mechanisms of age-dependent cognitive decline and Alzheimer’s disease pathogenesis and (2) determine whether cellular senescence contributes to cerebrovascular and cognitive dysfunction. Age-related deterioration of the cerebrovasculature is an important contributor to cognitive decline and Alzheimer’s disease, but targetable underlying mechanisms have yet to be discovered. Cellular senescence has emerged as a unifying feature of aging and numerous age-related conditions. Through the senescence-associated secretory phenotype (SASP), senescent cells impair tissue structure and function. Despite the well-known relationships between age-related vascular decline and cognition, whether and how senescent cells and the SASP contribute to cerebrovascular and cognitive dysfunction has not been explored. The proposed project will use young (6 months) and aged (26 months) p16-Ink-Attac mice, in which senescent cells can be GFP-monitored or deleted. We will also test the effects of senolytic drugs, which kill senescent cells. Parallel transgenic and pharmacological elimination strategies will enable us to mechanistical- ly explore the identity and effects of senescent cells. Aim 1 will identify the cell types that senesce in brain aging and will compare transgenic and senolytic cell clearance efficiency across cell populations in vivo. Aim 2 will leverage in vivo and in vitro experiments to test the hypothesis that senescent cerebrovascular cells secrete a proremodeling and proinflammatory SASP, which promotes BBB permeability and inflammation and may be alleviated by senescent cell clearance. Aim 3 will test the hypothesis that senescent cell removal improves vasomotor and cognitive function in aged mice. The K99 phase will be conducted at Mayo Clinic and will focus on obtaining mentored training in methods required to complete the proposed aims, conducting in vitro and in vivo experiments, and publishing cell-type profiling and in vitro results. The R00 phase will be conducted in my independent lab and will focus on analyzing mouse tissues and data, publishing all in vivo findings, and developing an R01 application based on these results. The proposed plan synergizes new skills in advanced imaging, vascular physiology, and cognitive testing with prior expertise in brain aging and cellular senescence to create a research trajectory that is distinct from my mentors’ foci. This work will produce a robust foundation for an independent research career elucidating cellular aging mechanisms and translatable solutions underlying cognitive decline and Alzheimer’s disease.

项目概要 该提案的目标是（1）获得开发所需的实验技能和职业培训 独立研究项目调查年龄依赖性认知衰退和阿尔茨海默病的机制 疾病发病机制以及（2）确定细胞衰老是否导致脑血管和 与年龄相关的脑血管退化是导致认知功能障碍的一个重要因素。 认知能力下降和阿尔茨海默病，但尚未发现可针对的潜在机制。 细胞衰老已成为衰老和许多与年龄相关的疾病的统一特征。 通过衰老相关的分泌表型（SASP），衰老细胞损害组织结构和 尽管年龄相关的血管衰退和认知之间存在众所周知的关系，但无论是 衰老细胞和 SASP 如何导致脑血管和认知功能障碍尚未得到证实 拟议的项目将使用年轻（6 个月）和老年（26 个月）的 p16-Ink-Attac 小鼠，其中 衰老细胞可以通过 GFP 进行监测或删除，我们还将测试可杀死细胞的衰老药物的效果。 并行的转基因和药物消除策略将使我们能够机械地- 探索衰老细胞的身份和影响 目标 1 将识别大脑中衰老的细胞类型。 衰老，并将比较体内细胞群的转基因细胞和衰老细胞清除效率。 将利用体内和体外实验来检验衰老脑血管细胞的假设 分泌促重塑和促炎 SASP，促进 BBB 通透性和炎症， 目标 3 将检验衰老细胞去除的假设。 改善老年小鼠的血管舒缩和认知功能 K99 阶段将在 Mayo Clinic 和 将侧重于获得完成拟议目标所需方法的指导培训， 体外和体内实验，并发布细胞类型分析和体外结果。 在我的独立实验室进行，重点分析小鼠组织和数据，发布所有体内 研究结果，并根据这些结果开发 R01 应用程序 拟议的计划可以协同新技能。 拥有先进成像、血管生理学和认知测试方面的专业知识，拥有脑老化和细胞方面的专业知识 这项工作将产生一个与我导师的重点不同的研究轨迹。 为阐明细胞衰老机制和可翻译的独立研究事业奠定了坚实的基础 认知能力下降和阿尔茨海默病的解决方案。