Impact of sex differences on the trajectory of interactome dysfunctions across the AD spectrum

性别差异对 AD 谱系中相互作用组功能障碍轨迹的影响

基本信息

批准号：
10300853
负责人：
GABRIELA CHIOSIS
金额：
$ 124.06万
依托单位：
SLOAN-KETTERING INST CAN RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-15 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10300853
关键词：
Address Affect Aging Alzheimer&apos s Disease Alzheimer&apos s disease brain Autopsy Bioinformatics Biological Biology Brain Brain region Cells Cerebellum Chemicals Clinical Cognitive Communities Complex Complex Analysis Computational algorithm Computer Analysis Data Data Analytics Data Set Defect Deposition Development Disease Environment Equipment and supply inventories Freezing Functional disorder Generations Genes Genotype Global Change Heterogeneity Hippocampus (Brain)Hormonal Human Image Impaired cognition Individual Knowledge Knowledge Portal Link Measures Metadata Mining Molecular Molecular Genetics Nature Nerve Degeneration Neuroglia Neurons Online Systems Outcome Output Pathologic Pathway interactions Patients Phenotype Phenotypic Sex Positioning Attribute Prevention Process Proteins Proteome Recording of previous events Resources Risk Factors Sampling Severities Sex Differences Site Sorting - Cell Movement Specimen System Technology Temporal Lobe Testing Time Transcript Translating biological systems brain cell brain tissue cell type comorbidity computerized data processing connectome data visualization design disease heterogeneity disease phenotype frontal lobe functional outcomes genome wide association study healthy aging innovation insight interest large scale data laser capture microdissection member mild cognitive impairment multidisciplinary network dysfunction novel strategies open source precision medicine protein protein interaction response sex spatiotemporal stoichiometry stressor therapy development user-friendly web platform

项目摘要

ABSTRACT The impact of sex differences in Alzheimer's disease (AD) remains poorly understood, especially in the context of protein-protein interactions within vulnerable regions that drive dysfunction. Despite growing appreciation of the clinical course, presentation, and severity of AD, studies of sex impacting AD development and progression are lacking. Although recent high-throughput and bioinformatics technologies help to understand molecular and genetic basis of sex differences in aging and AD, reliance on static `omics data representing a descriptive inventory of biomolecules measuring changes in their stoichiometry at a given time and condition limits functional insights. Another roadblock is translating these complex datasets into biological insights requires sophisticated computational algorithms, diminishing access and impact to the biomedical community at large. To address these limitations this proposal introduces epichaperomics, an unbiased state-of-the-art `omics approach we invented to generate direct access to interactome perturbations and to the functional outcome of such changes in native biological systems. We posit by applying epichaperomics to well-characterized postmortem human brains that i) capture the disease trajectory, ii) encompass AD vulnerable and less affected regions, and iii) have robust parallel information on patient-specific correlates, will enable rigorous hypothesis- generating analyses on potential impact of stressors and vulnerabilities on disease trajectory, and on interactome as well as connectome dysfunctions as they occur in sex-dependent manner. Through this novel approach we expect to derive mechanistic innovation on specific dysfunctions impacted by sex differences leading to insights into sex-phenotype relationships not available through other `omics platforms. By evaluating, understanding, and anticipating interactome changes through epichaperome formation in relation to sex impact (Aim 1) and subsequent straightforward computational analysis with web-based output (Aim 2), first-of-a-kind proteome-wide insights into the impact of sex differences on interactome networks vulnerabilities and dysfunctions within the hippocampus and regions of the default mode network in relation to the relatively spared cerebellum, both on their nature and trajectory, in vulnerable cells and brain regions will be generated. Information how stressors and vulnerabilities (e.g., genes, environment, hormonal status) interact at cell and brain connectome levels to produce heterogeneous phenotype mapping of disease vulnerability will be produced. We posit a whole new treatment paradigm avenue will open, providing a previously unavailable sex-specific precision medicine approach to AD by understanding and targeting the interactome across the AD spectrum of no cognitive impairment, mild cognitive impairment, and AD dementia through stressor and vulnerability analysis. Raw datasets and data analytics from interactome network studies will be deposited into free-access portals accessible by the scientific community for additional mining and hypothesis testing studies. A web-based user- interface will also be designed facilitating data processing and visualization.

抽象的性别差异在阿尔茨海默氏病（AD）中的影响仍然很少，尤其是在上下文中易受功能障碍区域内的蛋白质 - 蛋白质相互作用的相互作用。尽管对 AD的临床课程，表现和严重程度，性影响广告发展和进展的研究缺乏。尽管最近的高通量和生物信息学技术有助于了解分子和性别差异和AD的性别差异的遗传基础，依赖静态`代表描述性的OMICS 在给定时间和条件限制功能的生物分子库存测量其化学计量的变化见解。另一个障碍是将这些复杂数据集转化为生物学见解，需要复杂的计算算法，对生物医学社区的访问减少和影响。为了解决这些局限我们发明的方法可以直接访问Interactome扰动和对功能结果天然生物系统的这种变化。我们通过将表皮学应用于特征良好 i）捕获疾病轨迹的事后人大脑，ii）涵盖广告脆弱性且受影响较小区域和iii）具有有关患者特异性相关性的强大并行信息，将实现严格的假设 - 对压力源和脆弱性对疾病轨迹的潜在影响以及对互动组的潜在影响进行分析以及连接器功能障碍以性依赖性方式发生。通过这种新颖的方法我们期望对受性别差异影响的特定功能障碍产生机械创新，从而导致见解通过其他“ Omics平台都无法获得性 - 表型关系。通过评估，理解和通过与性影响相关的伴侣形成，预测相互作用的变化（AIM 1）和随后使用基于Web的输出（AIM 2），全蛋白质组的直接计算分析（AIM 2）对性别差异对互动网络的影响的见解与相对较低的小脑有关的海马和默认模式网络的区域，两者都在它们的性质和轨迹将在脆弱的细胞和大脑区域中产生。信息如何压力源和漏洞（例如基因，环境，激素状态）在细胞和脑连接素水平上相互作用将产生疾病脆弱性的异质表型映射。我们认为一个全新治疗范式大道将开放，提供以前不可用的性别精确药物通过理解和靶向无认知的AD频谱中的相互作用组来实现AD的方法通过压力源和脆弱性分析，损害，轻度认知障碍和AD痴呆症。生的来自Interactome网络研究的数据集和数据分析将沉积到自由访问门户网站科学界可以访问其他采矿和假设检验研究。基于网络的用户 - 界面还将设计促进数据处理和可视化。