Identifying the molecular systems, networks, and key molecules that underlie cognitive resilience

拟议的研究：确定分子系统、网络和关键分子 潜在的认知弹性是对RFA-AG-17-061的回应。该计划的总体目标 建议的研究是确定对AD、其他疾病的复原力的分子网络 与年龄相关的神经病理和与复原力相关的危险因素。这个 提案高度响应RFA，因为它侧重于网络的功能 支持认知韧性。具体地说，我们将生成高维分子数据， 我们将对其应用系统生物学方法，然后将其与 恢复力依赖于纵向认知数据和与年龄相关的神经病理分析。一个 这项研究的主要结果将是将环境、生活方式和体验因素与 特定的分子网络。除了在人体内验证蛋白质外，我们还将利用活的 人脑网络作为一种验证的“模型系统”。我们能够做到这一点，因为对于 第一次我们的组学将从以前提供功能磁共振数据的人那里获得。 因此，我们可以在弹性脑功能的基础上提供一个统一的视角 分子和大脑网络，它提供高度可信的经过验证的分子和 推动人类对阿尔茨海默病和与年龄相关的神经病理的韧性的网络。 我们建议的研究的主要资源是两项关于老龄化的纵向研究，它们 提供神经成像、基因组详细的神经病理、纵向认知评分和 量化衡量每个人的复原力。从这些队列中，我们将在目标1中获得 RNAseq和TMT蛋白质组学(9000个测量到的蛋白质)来自大脑的以下区域 根据核磁共振成像，分子结构的变化与弹性的连续测量同步 这群人中的一个。在确定了活跃在这些区域的分子系统之后，我们将(目标2) 推断每个分子系统中包含的网络，分子之间的连接 系统，以及分子系统和弹性之间的联系。考虑到这些限制 在验证认知表型的动物模型中，我们利用一个独特的资源来验证 基因和蛋白质网络被发现与韧性有关。我们将(目标3)使用动态 基于功能磁共振成像的大脑网络，以前从相同的人那里获得，以验证后- 死亡分子网络与认知功能的这一密切代理。因此，该提案带来了 关于弹性的几个主要观点-纵向认知，神经病理学， 多重组学和神经成像，以确定刺激复原力的新网络和靶点 并在赛场上产生强大而持久的影响。

The proposed study: Identifying the molecular systems, networks, and key molecules that underlie cognitive resilience is in response to RFA-AG-17-061. The overall goal of the proposed study is to identify the molecular networks underlying resilience to AD, other age-associated neuropathologies and risk factors associated with resilience. The proposal is highly responsive to the RFA in that it is focused on the function of networks supporting cognitive resilience. Specifically, we will generate high-dimensional molecular data, to which we will apply systems biology approaches, and then integrate these with measures of resilience that rely on longitudinal cognitive data and assays of age-related neuropathologies. A key outcome of this research will be linking environmental, lifestyle and experiential factors to specific molecular networks. In addition to protein validation in humans, we will utilize living human brain networks as a validation “model system”. We are able to do this, because for the first time our omics will be acquired from persons who previously provided fMRI data. Therefore, we can provide a unified perspective on the basis of resilient brain function in molecular and brain networks, which provides high confidence validated molecules and networks driving resilience to AD and age-related neuropathologies in humans. Our main resources for the proposed study are two longitudinal studies of aging, which provide neuroimaging, omic detailed neuropathology, longitudinal cognition scores and a quantitative measure of resilience for each person. From these cohorts, in Aim 1 we will acquire RNAseq and TMT proteomics (9000+ measured proteins) from regions of the brain whose molecular structure varies in synchrony with a continuous measure of resilience, based on MRI of this cohort. After identifying the molecular systems active in these regions, we will (Aim 2) infer the networks contained within each molecular system, the connections between molecular systems, and the connections between molecular systems and resilience. Given the limitations of animal models in validating cognitive phenotypes, we utilize a unique resource to validate the gene and protein networks found to be associated with resilience. We will (Aim 3) use dynamic fMRI-based brain networks, previously acquired from the same individuals to validate the post- mortem molecular networks with this close proxy of cognitive function. Thus the proposal brings to bear several major perspectives on resilience – longitudinal cognition, neuropathology, multiple omics and neuroimaging to identify novel networks and targets to stimulate resilience and producing a strong and sustained impact on the field.