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

总体项目摘要 到目前为止，衰老是发展各种神经退行性疾病的最重要驱动因素和风险因素。 疾病，包括阿尔茨海默病（AD）和相关痴呆。这些毁灭性的疾病 对患者及其家属造成了巨大的情感、社会和经济损失，但迄今为止， 这些治疗可以延迟，更不用说逆转这些疾病的发作或进展。显然，新的方法 了解和治疗与年龄相关的神经退行性变是必要的。项目资助（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。拟议的方案规划补助金包括： 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，这对大脑功能至关重要： 1)细胞命运决定，特别是细胞死亡和细胞衰老; 2）代谢，特别是反应 导致代谢重编程和炎症;以及3）细胞-细胞相互作用，特别是相互作用 神经元和非神经元细胞之间的联系。我们建议以行政方式支持这些计划， 核心，还将提供统计和生物信息学支持，以及三个科学核心：1）一个 iPSC/类器官核心; 2）蛋白质组学和代谢核心;以及3）单细胞和空间转录组学核心 核心PPG受益于项目和核心领导人和共同领导人的异常多样化的专业知识， 他们都是当代老龄化研究领域公认的领导者。每个项目都是一个结束 这是PPG几个成员之间的合作，其中许多人都有富有成效的合作历史。中的每 科学核心将为项目提供最先进的支持，使概念和技术 这些进步很难孤立地实现。项目和核心共同具有以下潜力： 发现AD和相关痴呆症的新机制，将在人类细胞和类器官中进行测试， 小鼠重要的是，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.