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: 8319503
• 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 2013-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8319503
• 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）：该提案是为了获得职业发展奖，使我能够从作为研究生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通路，过渡到专注于阿尔茨海默氏病（AD）的研究，同时继续追求建立独立研究项目的职业目标。我的导师郑辉博士慷慨地接受了我关于这一提议的培训，她出于对人类 AD 和小鼠 AD 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。由于靠近行为核心设施，并且其主任和该提案的共同导师 Rich Paylor 博士拥有专业知识，因此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内，我将有机会接受有关 AD 患者临床问题的培训，顾问为 Rachelle Doody 博士和神经病理学家 J Clay Goodman 博士。从这个由知名科学家组成的优秀团队中，我将接受阿尔茨海默氏病研究的细胞、行为和临床方法方面的最佳培训，同时通过研究阿尔茨海默氏症发生和进展过程中神经内分泌应激途径的破坏来最大限度地利用我过去的培训。阿尔茨海默病被认为是一种神经元退化疾病，患者会丧失记忆、身体功能和生计，从而丧失工作能力。虽然在了解 AD 患者的记忆形成和保留如何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丧失而出现失调的情况知之甚少。众所周知，AD 患者的内分泌回路之一是下丘脑-垂体-肾上腺 (HPA) 轴，它控制皮质醇的释放以应对压力。在本提案中，我详细介绍了一组实验，这些实验将提供有关 AD 小鼠模型中响应压力和控制 HPA 轴活动的神经元系统如何被错误调节的信息，以及压力如何影响 AD 相关病理的进展。实验方法分为三部分。首先，我计划描述携带家族性阿尔茨海默氏病 (FAD) 突变（获得 AD 病理）的衰老小鼠的特征，以了解焦虑相关行为、HPA 轴功能和压力系统调节的分子指标的变化。这些观察结果将使我能够确定 AD 病理的易感性和获得性改变应力轴功能的程度。其次，我将对模型动物施加压力，并确定这如何改变 AD 相关病理的测量，例如淀粉样斑块形成、神经原纤维缠结样病理和神经元变性。在第三个目标中，我将从遗传和药理学角度消除 HPA 轴的活性，并确定这是否可以改善 AD 病理的进展和认知能力下降。本提案中描述的实验借鉴了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。该提案的资助将使我能够获得阿尔茨海默病研究领域的新培训，并获得阿尔茨海默病神经病理学分析和行为表征的技能。总而言之，该提案描述了一个培训和研究计划，它将引导我的职业生涯更上一层楼，并使我能够顺利过渡到独立研究职位，同时建立 AD 应激生物学研究项目。 公共健康相关性：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现有的降压药物治疗阿尔茨海默病。