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

识别认知弹性背后的分子系统、网络和关键分子

• 批准号: 9439572
• 负责人: Christopher A. Gaiteri
• 金额: $ 91.79万
• 依托单位: RUSH UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-15 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9439572
• 关键词: Affect; Age; Aging; Alzheimer' s Disease; Animal Model; Automobile Driving; Autopsy; Base of the Brain; Biological; Biological Assay; Biological Models; Biological Process; Brain; Brain region; Cerebrovascular Disorders; Cessation of life; Characteristics; Clinical; Clinical/Radiologic; Cognition; Cognitive; Cohort Studies; Communities; Data; Dementia; Disease; Elderly; Freezing; Functional Magnetic Resonance Imaging; Fusiform gyrus; Gene Proteins; Goals; Human; Impaired cognition; Individual; Life Style; Link; Longitudinal Studies; Magnetic Resonance Imaging; Measures; Memory; Molecular; Molecular Structure; Neurodegenerative Disorders; Outcomes Research; Participant; Pathologic; Pathology; Pattern; Persons; Phenotype; Protein Region; Proteins; Proteome; Proteomics; Proxy; Religion and Spirituality; Resources; Risk Factors; System; Systems Biology; Testing; Therapeutic; Time; Ursidae Family; Validation; Work; age related; base; cognitive function; cognitive process; cohort; high dimensionality; in vivo; indexing; innovation; member; molecular marker; multiple omics; neuroimaging; neuropathology; novel; psychologic; resilience; response; support network; targeted treatment; therapeutic development; transcriptome; transcriptome sequencing

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.

抽象的 拟议的研究：识别认知基础的分子系统，网络和关键分子 弹性是为了回应 RFA-AG-17-061。 拟议研究的总体目标是确定 对AD的弹性，其他年龄相关的神经病理学和风险的分子网络 与弹性有关的因素。 该提案对RFA的反应很高，因为它的重点是 支持认知弹性的网络功能。具体来说，我们会的 产生高维分子 数据，我们将采用系统生物学方法，然后将这些方法与弹性衡量 依赖于纵向认知数据和与年龄有关的神经病理学的测定。一个关键结果 研究将将环境，生活方式和专家因素与特定分子网络联系起来。在 除了人类的蛋白质验证外，我们还将利用活着的人脑网络作为验证“模型 系统”。我们能够做到这一点，b 因为这是第一次将我们的omics从 以前提供了fMRI数据。因此，我们可以根据弹性大脑提供统一的观点 在分子和大脑网络中的功能，可提供高度置信度验证的分子和网络 在人类中推动对AD和与年龄相关的神经病理学的弹性。 我们提出的研究的主要资源是两项纵向研究，这些研究提供神经影像学，，即 OMIC详细的神经病理学，纵向认知评分和每种弹性的定量衡量标准 人。从这些队列中，在AIM 1中，我们将获取RNASEQ和TMT蛋白质组学（测得的9000多个 蛋白质）来自大脑区域的分子结构随着连续测量的同步而变化 弹性，基于此队列的MRI。在确定了这些区域中活跃的分子系统之后，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，以及分子系统与弹性之间的连接。考虑到动物的局限 验证认知表型的模型，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（AIM 3）使用基于FMRI的动态大脑网络， 以前从同一个人获得以验证验证后分子网络的情况 认知功能的代理。该提议带来了关于弹性的几个主要观点 - 纵向认知，神经病理学，多种OMICS和神经影像学以识别新型网络和目标 为了刺激韧性，对现场产生强烈而持续的影响。