Central and Endocrine Stress Pathway Contributions to Alzheimers Disease

描述（由申请人提供）：这个建议是一个职业发展奖，将允许我从研究生学习果蝇遗传学和神经内分泌应激途径作为博士后研究员的过渡，研究重点是阿尔茨海默病（AD），同时继续追求建立一个独立的研究计划的职业目标。我的导师Hui Zheng博士欣然接受了我的培训，他对人类AD和AD小鼠模型的应激表型感兴趣，招募我到她的实验室研究这些表型。由于靠近行为核心设施，以及其主任和该提案的共同导师Rich Paylor博士的专业知识，该环境非常适合该项目。此外，贝勒医学院位于得克萨斯州医学中心，我将有机会获得培训，在临床问题周围的人类患者患有AD与顾问的建议博士雷切尔杜迪和神经病理学家，博士J克莱古德曼。从这个优秀的科学家团队中，我将接受阿尔茨海默病研究的细胞，行为和临床方法的最佳培训，同时通过调查AD发展和进展中神经内分泌应激途径的中断来最大限度地提高我过去的培训。阿尔茨海默病被认为是一种神经元变性疾病，可以通过丧失记忆，身体功能和生计使其受害者丧失能力。虽然在了解AD患者的记忆形成和保留如何丢失方面取得了很大进展，但对神经元丢失时内分泌回路如何受到错误调节知之甚少。已知在AD患者中被破坏的这些内分泌回路之一是下丘脑-垂体-肾上腺（HPA）轴，其控制皮质醇响应于压力的释放。在这个建议中，我详细介绍了一组实验，将提供有关如何神经元系统，响应压力和控制HPA轴的活动是错误的调节在AD小鼠模型，以及压力如何影响AD相关的病理进展的信息。实验方法将分为三个方面。首先，我计划表征携带家族性阿尔茨海默病（FAD）突变的衰老小鼠，这些突变获得了AD病理，用于焦虑相关行为，HPA轴功能和压力系统调节的分子测量仪的变化。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。第二，我将应用应激模型动物，并确定如何改变AD相关的病理措施，如淀粉样斑块形成，神经元缠结样病理，神经元变性。在第三个目标中，我将从遗传学上消除HPA轴的活性，并确定这是否能改善AD病理和认知能力下降的进展。本提案中描述的实验来自我在果蝇和小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。这项提案的资助将使我在阿尔茨海默病研究领域获得新的培训，并获得AD的神经病理学分析和行为表征方面的技能。总的来说，这个建议描述了一个培训和研究计划，将指导我的职业生涯到一个新的水平，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的压力生物学的研究计划。 公共卫生相关性：该项目将研究压力增加是否会导致阿尔茨海默病，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.