Central and endocrine stress pathway contributions to Alzheimers Disease

中枢和内分泌应激通路对阿尔茨海默病的影响

• 批准号: 8149854
• 负责人: NICHOLAS J JUSTICE
• 金额: $ 12.55万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-30 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8149854
• 关键词: Acute; Adrenal Cortex Hormones; Adrenal Glands; Aging; Alleles; Alzheimer' s Disease; Alzheimer' s disease model; Amygdaloid structure; Amyloid beta-Protein Precursor; Anatomy; Animal Model; Animals; Anxiety; Automobile Driving; Behavior; Behavioral; Biology; Brain; Cell Nucleus; Chronic; Chronic stress; Clinical; Cognition; Cognitive; Cognitive deficits; Core Facility; Dementia; Development; Disease; Disease Progression; Drosophila genus; Endocrine; Endocrine system; Environment; Fright; Funding; Genetic; Goals; Hippocampus (Brain); Hormones; Human; Hydrocortisone; Hypothalamic structure; Impaired cognition; K-Series Research Career Programs; Knock-in Mouse; Learning; Link; Measures; Medical center; Medicine; Memory; Memory Loss; Mental Depression; Mentors; Molecular; Mus; Mutation; Nerve Degeneration; Neuroendocrinology; Neurons; Neurosecretory Systems; Outcome Study; Pathogenesis; Pathology; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Pituitary Gland; Positioning Attribute; Postdoctoral Fellow; Predisposition; Recruitment Activity; Regulation; Research; Research Training; Rest; Role; Scientist; Senile Plaques; Series; Severities; Severity of illness; Signal Transduction; Staging; Stress; Stress Tests; Synapses; System; Testing; Texas; Therapeutic; Time; Training; Work; acute stress; attenuation; biological adaptation to stress; career; clay; cognitive function; college; density; experience; familial Alzheimer disease; graduate student; hypothalamic-pituitary-adrenal axis; improved; insight; interest; mouse model; neurofibrillary tangle formation; neuronal circuitry; neuropathology; novel; null mutation; presenilin-1; programs; public health relevance; research study; response; skills; stressor

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.

描述（由申请人提供）：这是一个职业发展奖的提案，它将允许我从研究果蝇遗传学的研究生和神经内分泌应激途径的博士后过渡到研究阿尔茨海默病（AD），同时继续追求建立一个独立研究项目的职业目标。我的导师郑慧博士很荣幸地接受了我的培训，她对人类阿尔茨海默病的应激表型和阿尔茨海默病的小鼠模型很感兴趣，她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，贝勒医学院位于德克萨斯医学中心，我将有机会在Rachelle Doody博士和神经病理学家J Clay Goodman博士的建议下，接受有关人类AD患者临床问题的培训。从这群优秀的知名科学家那里，我将在阿尔茨海默病的细胞、行为和临床研究方法方面接受最好的训练，同时通过研究阿尔茨海默病发展和进展中神经内分泌应激途径的破坏，最大限度地发挥我过去的训练。阿尔茨海默病被认为是一种神经元退化的疾病，它可以通过失去记忆、身体功能和生计而使患者丧失能力。虽然在了解阿尔茨海默病患者的记忆形成和保持是如何丧失方面已经取得了很大进展，但关于内分泌回路是如何随着神经元丧失而失调的，我们所知甚少。其中一个已知在AD患者中被破坏的内分泌回路是下丘脑-垂体-肾上腺（HPA）轴，它控制应激时皮质醇的释放。在本文中，我详细介绍了一组实验，这些实验将提供有关在AD小鼠模型中如何对应激作出反应并控制HPA轴活动的神经元系统进行错误调节的信息，以及应激如何影响AD相关病理的进展。实验方法将有三个方面。首先，我计划对携带家族性阿尔茨海默病（FAD）突变并获得AD病理的衰老小鼠进行表征，研究焦虑相关行为、HPA轴功能和应激系统调节分子测量的变化。这些观察结果将使我能够确定AD病理的易感性和获得性改变应激轴功能的程度。其次，我将把压力源应用于模型动物，并确定这如何改变AD相关病理的测量，如淀粉样斑块形成、神经原纤维缠结样病理和神经元变性。在第三个目标中，我将从基因和药理学上切除HPA轴的活性，并确定这是否能改善AD病理的进展和认知能力下降。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神经病理分析和行为表征的技能。综上所述，这份提案描述了一个培训和研究计划，将指导我的职业生涯进入下一个阶段，并使我能够顺利过渡到一个独立的研究岗位，同时建立一个关于AD应激生物学的研究项目。