Investigating the Role of p21-Highly Expressing Senescent Cells in Alzheimer's Dementia

研究 p21 高表达衰老细胞在阿尔茨海默氏痴呆中的作用

基本信息

批准号：
10606953
负责人：
Nathan Gasek
金额：
$ 4.32万
依托单位：
UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-04-15 至 2027-04-14
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10606953
关键词：
APP-PS1 Address Age Aging Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease model Alzheimer&apos s disease risk Amyloid Amyloid beta-Protein Animals Apoptotic Automobile Driving Behavioral Biological Assay Biology of Aging Brain Cell Aging Cell Cycle Cell Cycle Proteins Cell Nucleus Cells Cessation of life Characteristics Cognitive Cognitive deficits Communication Computer Analysis Data Dementia Deposition Development Development Plans Disease Elderly Enterobacteria phage P1 Cre recombinase Excision Fluorescence Functional disorder Future Genetic Transcription Goals Growth Health Heterogeneity Histologic Human Immunohistochemistry Impaired cognition Impairment Inflammatory Link Literature LoxP-flanked allele Mentorship Metabolic Diseases Metabolic stress Modeling Molecular Morbidity - disease rate Mus Neurodegenerative Disorders Neurons Oxidative Stress Pathogenesis Pathology Pathway interactions Performance Physicians Play Population Process Production Proteins Reporter Research Resistance Resolution Role Scientist Senile Plaques System Testing Tissues Toxin Training Transgenic Mice Transgenic Organisms Work age related burden of illness career career development cell type clinical practice effective therapy experimental study improved inducible Cre insight mortality mouse model neuroinflammation neuron loss new therapeutic target novel novel therapeutics pharmacologic prevent promoter regenerative senescence single cell sequencing single nucleus RNA-sequencing stressor suicide gene tau Proteins tau aggregation therapeutic target timeline wasting

项目摘要

PROJECT SUMMARY/ABSTRACT Alzheimer’s Dementia (AD) is a leading cause of morbidity and mortality that is incompletely understood and lacking effective treatment. Accumulation of senescent cells (SnCs) has recently been implicated in AD pathogenesis and targeted removal of these cells may offer new therapeutic avenues. Cellular senescence is a cell fate defined by stable proliferative arrest, apoptotic resistance, and production of a pro-inflammatory secretome. Though senescence programming can contribute to proper development and regenerative processes, its dysregulation is increasingly linked with disease burden and pathology, including AD. While SnC modulation and clearance is a promising therapeutic target, it is increasingly clear that these cells are highly heterogeneous in their characteristics and function. We recently developed a mouse model to characterize a unique population of SnCs that highly express the cell cycle blockade protein p21 (p21high cells) and demonstrated that these cells play a causal role in age related physical dysfunction and metabolic disease. Furthermore, other literature has implicated clearance of pan-SnCs, which include p21high subpopulations, with cognitive improvements in AD. However, it is unknown if p21high cells make distinct contributions to AD or if their targeted removal can further counteract AD pathology. Therefore, this proposal aims to investigate the specific contributions of p21high SnCs to AD. Preliminary experiments have demonstrated that p21high cells accumulate in the brain of mouse AD models featuring amyloid- β plaque. However, it is unknown when these cells begin to accumulate in relation to the underlying disease process and what cell types are undergoing senescence. Therefore, in Aim 1, we will define the precise timeline of p21high cell accumulation in relation to amyloid- β plaque deposition (1A) and determine what cell types these represent (1B) by tracking these cells with a transgenic fluorescence reporter system and immunohistochemistry. To understand if these p21high SnCs play a causal role in AD, in Aim 2 we propose to selectively eliminate these cells via an inducible suicide gene to determine if targeted removal of these cells can either prevent (2A) or alleviate (2B) AD associated amyloid- β plaque formation and impaired performance on cognitive assays. We will also conduct single nuclei RNA sequencing (2C) on brains with or without p21high cell elimination to assess for changes in AD associated neuro-inflammatory pathways and explore underlying disease mechanisms associated with p21high cells. These aims will help to define the role of p21high SnCs in AD and may serve as a basis for new targeted disease modulating therapy. Furthermore, these results will further implicate p21high cells in age related disease and broaden the field’s appreciation of SnC heterogeneity. This work is part of a tailored career development plan at UConn Health that integrates training in aging biology, computational analysis, scientific communication, mentorship, clinical practice, and more to advance my career as a future physician-scientist that studies the drivers of aging.

项目概要/摘要阿尔茨海默氏痴呆 (AD) 是发病率和死亡率的主要原因，目前人们对其的认识尚不完全，缺乏有效的治疗方法最近发现衰老细胞（SnC）的积累与AD有关。这些细胞的发病机制和靶向去除可能会提供新的治疗途径。细胞命运由稳定的增殖停滞、凋亡抵抗和促炎物质的产生来定义尽管衰老编程有助于正常发育和再生。过程中，其失调与疾病负担和病理学（包括 AD）越来越相关。调节和清除是一个有前途的治疗靶点，越来越清楚的是，这些细胞具有高度我们最近开发了一种小鼠模型来表征它们的特征和功能。高度表达细胞周期阻断蛋白 p21 的独特 SnC 群体（p21high 细胞）和这些细胞在与年龄相关的身体功能障碍和代谢疾病中发挥着因果作用。此外，其他文献也暗示了泛 SnC 的清除，其中包括 p21high 亚群，然而，目前尚不清楚 p21high 细胞是否对 AD 有明显的贡献，或者它们的作用是否显着。有针对性的去除可以进一步抵消AD病理，因此，本提案旨在研究具体的。 p21high SnCs 对 AD 的贡献初步实验表明 p21high 细胞在 AD 中积累。然而，尚不清楚这些细胞何时开始形成。积累与潜在的疾病过程以及正在经历衰老的细胞类型有关。因此，在目标 1 中，我们将定义与淀粉样蛋白-β 斑块相关的 p21high 细胞积累的精确时间线沉积 (1A) 并通过使用转基因追踪这些细胞来确定这些细胞代表什么细胞类型 (1B) 荧光报告系统和免疫组织化学了解这些 p21high SnC 是否发挥因果作用。在 AD 中，在目标 2 中，我们建议通过诱导自杀基因选择性地消除这些细胞，以确定是否有针对性地去除这些细胞可以预防 (2A) 或减轻 (2B) AD 相关的淀粉样蛋白-β 斑块我们还将进行单核 RNA 测序。 (2C) 在有或没有 p21high 细胞消除的大脑上评估 AD 相关神经炎症的变化途径并探索与 p21high 细胞相关的潜在疾病机制。定义了 p21high SnCs 在 AD 中的作用，并可作为新的靶向疾病调节治疗的基础。此外，这些结果将进一步表明 p21high 细胞与年龄相关疾病的相关性，并拓宽该领域的研究范围。这项工作是康涅狄格大学健康中心量身定制的职业发展计划的一部分。整合了衰老生物学、计算分析、科学交流、指导、临床等方面的培训实践，以及更多，以推进我作为一名研究衰老驱动因素的未来医生科学家的职业生涯。