Identifying the origins of resilience through human single cell molecular networks, then testing them in diverse, resilient, human IPS lines

通过人类单细胞分子网络识别恢复力的起源，然后在多样化、有恢复力的人类 IPS 系中对其进行测试

• 批准号: 10730100
• 负责人: Christopher A. Gaiteri
• 金额: $ 47.72万
• 依托单位: UPSTATE MEDICAL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-30 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10730100
• 关键词: Identifying; origins; resilience; through; human

PROJECT SUMMARY Much of late-life cognitive decline cannot be explained by Alzheimer’s disease (AD) or other common age- related neuropathologies. In fact, every individual is either resilient or susceptible to AD to a certain extent, due to their unique genetics and environment. Over the past 15 years our center has identified numerous environmental and psychological risk factors associated with faster or slower cognitive decline, and several molecular markers of resilience, that point to the existence of molecular networks that underlie resilience. The proposed project builds on this prior work. The overall goal of this proposal is to define the complex molecular basis of resilience to AD, using brains with various levels of resilience and in vitro human model systems, to identify novel therapeutic targets for cognitive decline. To do this, we will take a genome-wide approach to identify key molecular drivers of resilience in specific cell types in the human brain. Then we will perform rigorous tests of the molecules we have identified using brain cells from many different humans. Specifically we will see if we can genetically stimulate these cells to become more resilient to the effects of aging and Alzheimer’s disease. Two key innovations separate this project from previous work. The first aspect is our focus on individual cell types. Typically molecular measurements of brain data contain a mixture of dozens of cell types. We will measure each of these cell types individually, using single-cell RNAseq (scRNAseq), to identify which cell types are most related to resilience to AD. Within these specific cell types we will use computational network analysis to identify a smaller number of gene genes within the molecular systems affecting resilience. These predictions facilitate the 2nd aspect of this study which is unusual, which is our plan to change these genes in a human model of AD. The model we will use are neurons and glial cells derived from 50 individuals with different level of resilience to the common sporadic form of Alzheimer’s. We will use genome engineering to affect the abundance of genes that we predict are related to resilience in all of these cell lines. In this way we can check for resulting gene expression signatures of resilience as well as cellular phenotypes associated with health cognition, which persist in the face of AD pathology. The proposed project will deliver a comprehensive set of molecular networks and key molecules that underlie resilience to AD and other common brain pathologies. It will do so by breaking common barriers to progress in this area: 1) accurate identification of targets through a single cell approach and computational network methods, and 2) testing in realistic human models. The proposed project will provide high-confidence targets for therapeutic development. Thus, the proposal will have a strong and sustained impact on the field.

项目总结 阿尔茨海默病(AD)或其他常见年龄无法解释晚年认知能力下降的原因-- 相关的神经病理学。事实上，每个人都在一定程度上对阿尔茨海默病具有韧性或易感性， 由于它们独特的遗传和环境。在过去的15年里，我们中心已经确认了许多 与认知能力下降更快或更慢相关的环境和心理风险因素，以及几个 韧性的分子标记，这表明存在构成韧性的分子网络。这个 拟议的项目建立在这一先前工作的基础上。这项提案的总体目标是定义综合体 AD复原力的分子基础，使用具有不同复原力水平的大脑和体外人类 模型系统，以确定认知功能下降的新治疗靶点。要做到这一点，我们将使用 全基因组方法，以确定人类大脑中特定细胞类型的弹性的关键分子驱动因素。 然后，我们将使用许多不同的脑细胞对我们已经识别的分子进行严格的测试 人类。具体地说，我们将看看我们是否能从基因上刺激这些细胞，使其对 衰老和阿尔茨海默病的影响。该项目与以前的工作相比有两个关键的创新。这个 第一个方面是我们对单个细胞类型的关注。通常，大脑数据的分子测量包含一个 几十种细胞类型的混合体。我们将使用单个细胞分别测量每种细胞类型 RNAseq(ScRNAseq)，以确定哪些细胞类型与AD的恢复力最相关。在这些特定的 细胞类型我们将使用计算网络分析来识别 影响弹性的分子系统。这些预测有助于这项研究的第二个方面，即 不同寻常，这就是我们计划在人类AD模型中改变这些基因的计划。我们将使用的模型是 来自50个个体的神经元和神经胶质细胞对常见的散发性疾病具有不同程度的弹性 阿尔茨海默氏症。我们将使用基因组工程来影响我们预测的基因的丰度 与所有这些细胞系的弹性有关。通过这种方式，我们可以检查所产生的基因表达签名 与健康认知相关的弹性以及与健康认知相关的细胞表型，在阿尔茨海默病面前持续存在 病理学。拟议的项目将提供一套全面的分子网络和关键分子 这是抵抗阿尔茨海默病和其他常见脑部疾病的基础。它将通过打破共同的障碍来做到这一点 要在这一领域取得进展：1)通过单细胞方法和计算方法准确识别目标 网络方法，以及2)在真实的人体模型中进行测试。拟议的项目将提供高度的信心 治疗发展的目标。因此，该提案将对实地产生强大和持久的影响。