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

细胞衰老和细胞命运/相互作用是阿尔茨海默氏症和年龄相关性痴呆的驱动因素

• 批准号: 10633021
• 负责人: Judith Campisi
• 金额: $ 8.35万
• 依托单位: BUCK INSTITUTE FOR RESEARCH ON AGING
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-30 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10633021
• 关键词: 3-Dimensional; Affect; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease related dementia; Applications Grants; Astrocytes; Automobile Driving; Bioinformatics; Brain; Cell Aging; Cell Communication; Cell Culture Techniques; Cell Death; Cells; Clinical; Cognition; Collaborations; Data; Dementia; Development; Disease; Disease Progression; Economics; Emotional; Endothelial Cells; Etiology; Family; Goals; Head; Human; Inflammation; Institutes; Intervention; Knowledge; Lead; Metabolic; Metabolism; Modeling; Molecular; Mus; Nature; Nerve Degeneration; Neurodegenerative Disorders; Neuroglia; Neurons; Oligodendroglia; Organoids; Pathology; Patients; Pharmaceutical Preparations; Phenotype; Population; Program Research Project Grants; Proteome; Proteomics; Publishing; Recording of previous events; Research; Research Personnel; Research Project Grants; Risk; Risk Factors; Role; Testing; Time; Translating; age related; age related neurodegeneration; aging brain; brain cell; cell type; cost; effective intervention; effective therapy; induced pluripotent stem cell; insight; interest; macrophage; member; metabolome; mouse model; novel; novel strategies; response; senescence; social; transcriptomics

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.

总体项目摘要 衰老是迄今为止开发各种神经退行性的最重要的驱动因素和风险因素 包括阿尔茨海默氏病（AD）和相关痴呆症在内的疾病。这些毁灭性疾病准确 巨大的情感，社会和经济对患者及其家人造成了巨大的伤害，但至今尚无有效 这些疾病的发作或进展的延迟，更少逆转的治疗方法。显然，新方法 需要理解和治疗与年龄相关的神经变性。该计划项目赠款（PPG） 提案旨在在我们的知识和治疗方法中填补这一严重的空白。拟议的PPG组成 在三个研究项目中，每个研究都集中在脑衰老的一个方面，该方面对大脑功能至关重要： 1）细胞脂肪决策，尤其是细胞死亡和细胞感应； 2）新陈代谢，特别是反应 导致代谢重编程和炎症； 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。我们建议通过行政管理支持这些项目 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） ipsc/starmoid核心； 2）蛋白质组学和代谢核心； 3）单个单元和空间转录组学 核。 PPG受益于该项目的异常专业知识以及核心领导者和共同领导者， 所有人都是当代衰老研究中的公认的领导者。每个项目都接近 几位PPG成员之间的合作，其中许多人都有产品合作的历史。每个 科学核心将为项目提供最先进的支持，从而实现概念和技术 进步将很难孤立地实现。共同的项目和核心有可能 发现AD和相关痴呆症的新机制，该机制将在人类细胞和类器官中进行测试以及 老鼠。重要的是，这些机制可以发展为可以使用的干预措施，以治疗人类患者。