Cellular senescence and cell fate/interactions as drivers of Alzheimer's and age-related dementias

整体项目总结 到目前为止，衰老是导致各种神经退行性变的最重要的驱动因素和风险因素 疾病，包括阿尔茨海默病(AD)和相关的痴呆。这些毁灭性的疾病恰好 给患者及其家人带来巨大的情感、社会和经济损失，但迄今为止还没有有效的 延缓，更不用说逆转这些疾病的发病或进展的治疗。显然，新的方法 了解和治疗年龄相关性神经退行性变是必要的。本计划项目补助金(PPG) 该提案旨在填补我们在知识和治疗方法方面的这一严重空白。拟议的PPG包括 在三个研究项目中，每个项目都专注于大脑老化的一个方面，这是已知的对大脑功能至关重要的方面： 1)细胞命运决定，特别是细胞死亡和细胞衰老；2)新陈代谢，特别是反应 导致代谢重新编程和炎症；以及3)细胞-细胞相互作用，特别是相互作用 在大脑中的神经元和非神经元细胞之间。我们建议由一个行政部门来支持这些项目 还将提供统计和生物信息学支持的核心，以及三个科学核心：1) IPSC/有机核心；2)蛋白质组和代谢核心；以及3)单细胞和空间转录组学 核心。PPG受益于项目以及核心领导和联合领导的异常多样化的专业知识， 他们都是当代老龄化研究中公认的领导者。每个项目都是一个结束语 几个PPG成员之间的协作，其中许多成员都有卓有成效的协作历史。每一个 科学核心将为项目提供最先进的支持，使概念和技术 在孤立的情况下难以实现的进步。总而言之，这些项目和核心有可能 发现阿尔茨海默病和相关痴呆的新机制，这将在人类细胞和有机物中进行测试，并 老鼠。重要的是，这些机制可以发展成可用于治疗人类患者的干预措施。

OVERALL PROJECT SUMMARY Aging is by far the most important driver and risk factor for developing a variety of neurodegenerative diseases, including Alzheimer’s disease (AD) and related dementias. These devastating diseases exact an enormous emotional, social and economic toll on patients and their families, yet to date there are no effective treatments that delay, much less reverse, the onset or progression of these diseases. Clearly, new approaches to understanding and treating age-related neurodegeneration are needed. This Program Project Grant (PPG) proposal aims to fill this serious gap in our knowledge and treatment approaches. The proposed PPG consists of three research projects, each focused on an aspect of brain aging that is known to be crucial for brain function: 1) cell fate decisions, particularly cell death and cellular senescence; 2) metabolism, particularly responses leading to metabolic reprogramming and inflammation; and 3) cell-cell interactions, particularly interactions between neurons and non-neuronal cells in the brain. We propose to support the projects by an administrative core, which will also provide statistical and bioinformatics support, and three scientific cores: 1) an iPSC/Organoid core; 2) a Proteomics and Metabolism core; and 3) a Single Cell and Spatial Transcriptomics core. The PPG benefits from the exceptionally diverse expertise of the Project and Core leaders and co-leaders, all of whom are acknowledged leaders in contemporary aging research. Each of the projects is a close collaboration among several PPG members, many of whom have a history of productive collaboration. Each of the scientific cores will provide state-of-the art support to the projects, enabling conceptual and technical advances that would be difficult to achieve in isolation. Together, the Projects and Cores have the potential to uncover new mechanisms of AD and related dementias, which will be tested in human cells and organoids and mice. Importantly, these mechanisms can be developed into interventions that can be used treat human patients.