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

摘要 拟议的研究：确定构成认知基础的分子系统、网络和关键分子 恢复力是对 RFA-AG-17-061。 拟议研究的总体目标是确定 阿尔茨海默病、其他与年龄相关的神经病理和风险的分子网络 与弹性相关的因素。 该提案高度响应了RFA，因为它侧重于 支持认知韧性的网络的功能。具体来说，我们将 产生高维分子 数据，我们将对其应用系统生物学方法，然后将这些数据与弹性测量相结合 这依赖于纵向认知数据和与年龄相关的神经病理分析。这件事的一个关键结果是 研究将把环境、生活方式和体验因素与特定的分子网络联系起来。在……里面 除了在人类中验证蛋白质外，我们还将利用活的人脑网络作为验证的模型 系统“。我们能够做到这一点，b 因为我们的基因组学将第一次从 之前提供的功能磁共振数据。因此，我们可以在弹性大脑的基础上提供一个统一的视角 在分子和大脑网络中发挥作用，提供高度可信的经过验证的分子和网络 推动人类对阿尔茨海默病和与年龄相关的神经病理的适应能力。 我们建议研究的主要资源是两项关于衰老的纵向研究，这两项研究提供了神经成像， OMIC详细的神经病理、纵向认知评分和弹性的量化测量 人。从这些队列中，在目标1中，我们将获得RNAseq和TMT蛋白质组学(9000测量 蛋白质)来自大脑的区域，其分子结构的变化与连续的 恢复力，基于这个队列的核磁共振。在确定了活跃在这些区域的分子系统后，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。考虑到动物的局限性 在验证认知表型的模型中，我们利用独特的资源来验证基因和蛋白质 被发现与复原力相关的网络。我们将(目标3)使用基于动态功能磁共振成像的大脑网络， 之前从相同的人那里获得的验证死后分子网络的近距离 认知功能的代理。因此，该提案带来了关于韧性的几个主要观点- 纵向认知、神经病理学、多重组学和神经成像以识别新的网络和靶点 激发复原力，在实地产生强大和持久的影响。

ABSTRACT 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, b ecause 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, producing a strong and sustained impact on the field.