Sex Differences in the Molecular Determinants of Alzheimer's Disease Risk: Prodromal Endophenotype

项目摘要/摘要 阿尔茨海默病风险的分子决定因素性别差异的使命：前驱症状 内表型项目是确定染色体性别和主要风险之间复杂的相互作用 晚发性阿尔茨海默病(LOAD)的影响因素：年龄、APOE*4基因和AD母亲病史。作为装货帐户 对于疾病的最大发病率和流行率，确定与负荷相关的分子机制 有可能产生最大的影响。此外，针对风险的早期过渡具有最大的潜力 以求治疗效果。因此，这里提出的研究集中在负荷的前驱/临床前阶段。 以及导致负荷进展的早期风险的性别差异。关于性别差异的阐释 驱动前驱物负荷的机制将导致识别治疗靶点以改变其运动轨迹 这种疾病可以预防、延缓和潜在地逆转发育负荷的进程。 为了实现这一目标，我们组建了一支具有跨性别专业知识的综合研究团队 在以下方面的差异：在临床前/前驱期负荷阶段出现的人脑成像内表型， 跨性别、年龄、载脂蛋白E和线粒体生物能量学的复杂相互作用的分子机制 创新的翻译AD动物模型开发、数据科学和计算系统生物学 生物信息学，以确定性别特定的内表型和治疗目标，以实现精确健康， 我们提出的研究计划是在三个具体目标上组织和整合的，旨在 确定先兆负荷中潜在的性别差异的复杂机制和途径 内表型。换言之，我们将我们的方法锚定在复杂的人类生物学和 将这种复杂性整合到一个创新的动物模型中，该模型结合了年龄、性别、载脂蛋白E*4等负荷风险因素 基因分型与母体线粒体DNA遗传。目标1将在脑前驱症状中建立性别差异 脑部PET和MRI成像与创新的线粒体31P-MRS成像并行的内表型研究 在人脑中的功能。AIM 2旨在机械地确定系统生物学途径和 在负载的前兆阶段出现的网络。利用UI-JAX模型-AD，我们将开发一种新颖的和 翻译上有效的负荷模型，解决了包括母系遗传在内的4个负荷风险因素中的每一个 通过母体线粒体基因组和生物能量能力的遗传导致AD(LOADm4：AGE MtDNA-Happ-hAPOEe4)。在目标3中，来自目标1和目标2的多尺度数据将使用创新和 灵敏的计算系统生物学方法检测先兆过渡期的性别差异 加载风险和治疗目标以降低风险。 我们的分析结果将阐明中年出现并增加风险的分子机制 在晚年患上阿尔茨海默病。总而言之，这些数据将为基于性别的精确度提供治疗目标 药物干预在负荷的前驱阶段，当潜在逆转、预防和延缓 加载进度是最大的。 这里提出的研究涉及国家阿尔茨海默氏症项目法(NPA)的目标，以预防和 到2025年有效治疗阿尔茨海默病和NIA阿尔茨海默病研究峰会2015年性关键目标 和AD的代谢决定因素。

PROJECT SUMMARY / ABSTRACT The mission for the Sex Differences in the Molecular Determinants of Alzheimer's Disease Risk: Prodromal Endophenotype project is to determine the complex interaction between chromosomal sex and the major risk factors for late onset Alzheimer’s (LOAD): age, APOE*4 genotype and maternal history of AD. As LOAD accounts for the greatest incidence and prevalence of the disease, determining molecular mechanisms relevant to LOAD has the potential for greatest impact. Further, targeting early stage transitions of risk have the greatest potential for therapeutic efficacy. Thus, research proposed herein focuses on the prodromal / preclinical stage of LOAD and the sex differences that underlie early risks of LOAD progression. Elucidation of sex differences in the mechanisms driving prodromal LOAD will lead to identification of therapeutic targets to change the trajectory of the disease to prevent, delay and potentially reverse course of developing LOAD. To achieve this goal, we have assembled an integrative research team with expertise spanning sex differences in: human brain imaging endophenotypes that emerge during pre-clinical / prodromal phase of LOAD, molecular mechanisms of complex interactions across sex, age, ApoE and mitochondrial bioenergetics and innovative translational AD animal model development, data science and computational systems biology bioinformatics to identify sex specific endophenotypes and therapeutic targets for precision health, Our proposed program of research is organized and integrated across three specific aims designed to determine the complex mechanisms and pathways underlying sex differences in the prodromal LOAD endophenotype. Translationally, we have anchored our approach in the complex biology of humans and integrated that complexity into an innovative animal model that combine LOAD risk factors of age, sex, APOE*4 genotype and maternal mitochondrial DNA inheritance. Aim 1 will establish sex differences in brain prodromal endophenotype using brain PET and MRI imaging in parallel with innovative 31P-MRS imaging of mitochondrial function in human brain. Aim 2 is designed to mechanistically determine the systems biology pathways and networks that emerge during the prodromal phase of LOAD. With UI-JAX Model-AD, we will develop a novel and translationally valid model of LOAD that addresses each of the 4 LOAD risk factors including maternal inheritance of AD through inheritance of the maternal mitochondrial genome and bioenergetic capacity (LOADm4: aged mtDNA-hAPP-hAPOEe4). In Aim 3, multi-scale data from Aims 1 and 2 will be analyzed using an innovative and sensitive computational systems biology approach to detect sex differences in the prodromal transition state of LOAD risk and therapeutic targets to mitigate risk. Outcomes of our analyses will elucidate molecular mechanisms that emerge in midlife and that increase risk of developing AD later in life. Collectively, these data will provide therapeutic targets for sex-based precision medicine interventions during the prodromal phase of LOAD, when the potential to reverse, prevent and delay LOAD progression is greatest. Research proposed herein address goals of the National Alzheimer's Project Act (NAPA) to prevent and effectively treat AD by 2025 and the NIA Alzheimer's Disease Research Summit 2015 key objectives of sex and metabolic determinants of AD.