Central and endocrine stress pathway contributions to Alzheimers Disease

描述(由申请人提供)：这项建议是为职业发展奖，将允许我从研究生时研究果蝇遗传学和作为博士后研究员研究神经内分泌应激途径，过渡到专注于阿尔茨海默病(AD)的研究，同时继续追求建立独立研究计划的职业目标。我已经被我的导师郑辉博士欣然接受了关于这项提议的培训，她通过对人类AD和AD小鼠模型的应激表型的兴趣，招募我到她的实验室工作，研究这些表型。这个环境非常适合这个项目，因为它靠近一个行为核心设施，而且它的主任和该项目的共同导师Rich Payeller博士具有专业知识。此外，贝勒医学院位于德克萨斯医学中心内，我将有机会与Rachelle Doody博士和神经病理学家J Clay Goodman博士一起接受有关阿尔茨海默病患者临床问题的培训。从这群优秀的科学家那里，我将接受研究阿尔茨海默病的细胞、行为和临床方法方面的最好培训，同时通过研究神经内分泌应激途径在阿尔茨海默病的发展和进展中的破坏，最大化我过去的培训。阿尔茨海默病被理解为一种神经元退行性疾病，可通过丧失记忆、身体功能和生计而使患者丧失行为能力。虽然在了解阿尔茨海默病患者记忆形成和保持能力的丧失方面已经取得了很大进展，但对于内分泌回路如何随着神经元的丧失而变得错误调节知之甚少。已知在AD患者中被破坏的内分泌回路之一是下丘脑-垂体-肾上腺轴(HPA)，它控制皮质醇的释放以应对压力。在这项提案中，我详细介绍了一系列实验，这些实验将提供有关AD小鼠模型中对应激反应和控制HPA轴活动的神经元系统如何被错误调节，以及应激如何影响AD相关病理进展的信息。实验方法将分为三个方面。首先，我计划描述携带家族性阿尔茨海默病(FAD)突变的老年小鼠的特征，这些突变获得AD病理，观察焦虑相关行为、HPA轴功能和压力系统调节的分子指标的变化。这些观察将使我能够确定AD病理的易感性和获得性改变应力轴功能的程度。其次，我将把应激源应用于模型动物，并确定这如何改变与AD相关的病理指标，如淀粉样斑块形成、神经纤维缠结样病理和神经元变性。在第三个目标中，我将从遗传和药物上消除HPA轴的活动，并确定这是否可以改善AD病理的进展和认知能力下降。这项提案中描述的实验来自我在果蝇和老鼠遗传学方面的经验，以及我在应激神经内分泌学领域的工作。这项计划的资金将使我能够在阿尔茨海默病研究领域获得新的培训，并获得AD的神经病理分析和行为特征方面的技能。综上所述，这项建议描述了一个培训和研究计划，将指导我的职业生涯更上一层楼，并允许我顺利过渡到一个独立的研究职位，同时建立一个关于AD应激生物学的研究计划。 公共卫生相关性：该项目将研究增加的压力是否会导致阿尔茨海默氏症，以及压力在疾病进展中的作用。这项研究的结果将有助于开发治疗阿尔茨海默病的新疗法，以及更好地了解如何使用目前可用的减压药物来治疗阿尔茨海默病。

DESCRIPTION (provided by applicant): This proposal is for a career development award that will allow my transition from studying genetics in Drosophila as a graduate student and neuroendocrine stress pathways as a post-doctoral fellow, to a research focus on Alzheimer's disease (AD), while continuing to pursue a career goal of establishing an independent research program. I have been graciously accepted for training by my mentor on this proposal, Dr. Hui Zheng, who, through an interest in stress phenotypes in human AD and mouse models of AD recruited me to work in her lab to investigate these phenotypes. The environment is ideal for this project due to the proximity of a behavioral core facility, and the expertise of its Director and a co-mentor on this proposal, Dr. Rich Paylor. In addition, Baylor College of Medicine is located within the Texas Medical Center, and I will have access to training in clinical issues surrounding human patients that suffer from AD with consultants on the proposal Dr. Rachelle Doody and a neuropathologist, Dr. J Clay Goodman. From this excellent group of well established scientists, I will receive the best training in cellular, behavioral, and clinical approaches to the study of Alzheimer's disease while maximizing my past training by investigating the disruption of neuroendocrine stress pathways in the development and progression of AD. Alzheimer's disease is understood as a disease of neuronal degeneration that can incapacitate its victim through the loss of memory, bodily function, and livelihood. While much progress has been made in understanding how memory formation and retention is lost in AD patients, less is known about how endocrine circuits become mis-regulated as neurons are lost. One of these endocrine circuits that is known to be disrupted in AD patients is the Hypothalamic-Pituitary-Adrenal (HPA) axis which controls cortisol release in response to stress. In this proposal, I detail a set of experiments that will provide information about how neuronal systems that respond to stress and control the activity of the HPA axis are mis-regulated in an AD mouse model, and how stress impacts the progression of AD related pathology. The experimental approach will be three fold. First, I plan to characterize aging mice carrying Familial Alzheimer's Disease (FAD) mutations that acquire AD pathologies, for changes in anxiety related behavior, HPA axis function, and molecular gauges of stress system regulation. These observations will allow me to determine the degree to which susceptibility and acquisition of AD pathologies alters stress axis function. Second, I will apply stressors to model animals, and determine how this changes measures of AD related pathology, such as amyloid plaque formation, neurofibrillary tangle-like pathology, and neuronal degeneration. In the third aim, I will genetically and pharmacologically ablate activity of the HPA axis, and determine if this ameliorates the progression of AD pathologies and cognitive decline. The experiments described in this proposal draw from my experience with Drosophila and mouse genetics and my work in the field of stress neuroendocrinology. Funding of this proposal will allow me to gain new training in the field of Alzheimer's Disease research, and acquire skills in neuropathological analysis and behavioral characterization of AD. Taken together, this proposal describes a training and research plan that will guide my career to the next level, and allow me to smoothly transition to an independent research position while establishing a research program on the stress biology of AD. PUBLIC HEALTH RELEVANCE: This project will study whether increased stress leads to Alzheimer's Disease, and the role that stress has in the progression of the disease. The results of this study will contribute to the development of new therapies for Alzheimer's disease as well as a better understanding of how to use currently available stress lowering medication in treating Alzheimer's Disease.