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

摘要 性别差异对阿尔茨海默病(AD)的影响仍然知之甚少，特别是在 导致功能障碍的脆弱区域内的蛋白质相互作用。尽管越来越多的人欣赏 阿尔茨海默病的临床病程、临床表现和严重程度，性别对阿尔茨海默病发生和进展的影响研究 都是缺乏的。尽管最近的高通量和生物信息学技术有助于理解分子和 衰老和阿尔茨海默病性别差异的遗传基础，依赖于代表描述性 测量生物分子在给定时间和条件下化学计量比变化的生物分子清单限制功能 洞察力。另一个障碍是将这些复杂的数据集转化为生物学洞察需要复杂的 计算算法，减少了对整个生物医学界的接触和影响。 为了解决这些局限性，这项建议引入了表观经济学，这是一种公正的最先进的组学 我们发明了一种方法来生成对交互作用组扰动和对函数结果的直接访问 原生生物系统中的这种变化。我们通过将表观经济学应用于描述良好的 死后人脑：i)捕捉疾病轨迹，ii)涵盖易受阿尔茨海默病影响的阿尔茨海默病 区域，以及iii)拥有关于患者特定相关性的稳健的平行信息，将使严格的假设成为可能- 对压力源和脆弱性对疾病轨迹和互动组的潜在影响进行分析 以及连接体功能障碍，因为它们以性别依赖的方式发生。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进行机制创新，从而获得洞察力 性别-表型关系，这是其他‘组学平台’所不能提供的。通过评估、了解和 预测通过上壳体形成的交互作用组变化与性影响(目标1)和 随后通过基于网络的输出进行直接的计算分析(目标2)，这是第一个在蛋白质组范围内实现的 洞察性别差异对互动组网络脆弱性和功能障碍的影响 海马体和默认模式网络的区域与相对备用的小脑有关，两者都在 它们的性质和轨迹，在脆弱的细胞和大脑区域将被产生。关于压力源和 脆弱性(如基因、环境、荷尔蒙状态)在细胞和大脑连接体水平上相互作用 将产生疾病易损性的异质表型图谱。我们假设了一个全新的 治疗范例大道将打开，提供以前无法获得的针对性别的精确医学 通过理解和定位无认知的AD谱系中的交互作用组来治疗AD 通过应激源和易损性分析，发现阿尔茨海默病、轻度认知损害和阿尔茨海默病。生品 来自互动组网络研究的数据集和数据分析将存储到免费访问门户中 科学界可以访问，以进行额外的挖掘和假设检验研究。基于Web的用户- 还将设计便于数据处理和可视化的界面。

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.