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

摘要 拟议的研究：识别认知的分子系统，网络和关键分子 弹性是对 RFA-AG-17-061。 拟议研究的总体目标是确定 分子网络是对AD、其他年龄相关神经病理学和风险的恢复力的基础 与弹性相关的因素。 该提案高度响应RFA，因为它侧重于 支持认知弹性的网络功能。具体来说，我们将 生成高维分子 数据，我们将应用系统生物学方法，然后将其与弹性措施相结合 这依赖于纵向认知数据和与年龄相关的神经病理学分析。一个关键的结果是， 研究将把环境、生活方式和经验因素与特定的分子网络联系起来。在 除了在人类中进行蛋白质验证外，我们还将利用活的人脑网络作为验证“模型 系统”。我们能做到的，B 因为这是第一次，我们的组学将从那些 先前提供的fMRI数据。因此，我们可以在弹性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，提供高置信度的验证分子和网络 推动人类对AD和年龄相关神经病理学的恢复力。 我们提出的研究的主要资源是两项关于衰老的纵向研究，它们提供了神经影像学， 详细的神经病理学，纵向认知评分和每个人的弹性定量测量 人.从这些群组中，在目标1中，我们将获得RNAseq和TMT蛋白质组学（9000+测量的 蛋白质），其分子结构与连续测量的 恢复力，基于该队列的MRI。在确定了这些区域中活跃的分子系统后，我们将 (Aim（二） 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。鉴于动物的局限性， 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， 发现网络与弹性有关。我们将（目标3）使用基于动态fMRI的大脑网络， 先前从相同的个体获得，以验证死后的分子网络， 认知功能的代理。因此，该提案提出了关于复原力的几个主要观点： 纵向认知，神经病理学，多组学和神经成像，以确定新的网络和目标 激发复原力，对实地产生强大和持续的影响。

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.