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）：该提案是为职业发展奖项提供的，该奖项将使我从研究果蝇的遗传学转变为研究生和神经内分泌压力途径作为博士后研究员，转换为对阿尔茨海默氏病（AD）的研究，同时继续追求一个职业生涯的目标。我的导师对这一提案的培训曾经接受了培训，郑郑博士通过对人类AD中的压力表型的兴趣和AD小鼠模型的兴趣，招募了我在她的实验室工作，以调查这些表型。由于行为核心设施的距离及其董事的专业知识及其该提案的联合学者Rich Paylor博士，因此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部，我将接受有关人类患者的临床问题培训，这些临床患者与顾问Rachelle Doody博士和神经病理学家J Clay Goodman博士有关。从这一出色的成熟科学家组中，我将获得对阿尔茨海默氏病的细胞，行为和临床方法的最佳培训，同时通过研究AD的发展和进展中神经内分泌压力途径的破坏，从而最大程度地提高了我过去的培训。阿尔茨海默氏病被理解为一种神经元变性的疾病，可以通过失去记忆，身体功能和生计使受害者失去受害者。尽管在了解AD患者中如何丢失记忆力和保留率方面已经取得了很大进展，但对于随着神经元的损失而言，内分泌电路如何被错误调节。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（HPA）轴，该轴控制了响应压力的皮质醇释放。在此提案中，我详细介绍了一组实验，这些实验将提供有关如何在AD小鼠模型中误导和控制HPA轴活动的神经元系统，以及压力如何影响AD相关病理的发展。实验方法将为三倍。首先，我计划表征携带家族性阿尔茨海默氏病（FAD）突变的老化小鼠，这些突变是获得AD病理学的变化，与焦虑相关行为，HPA轴功能和压力系统调节的分子计的变化。这些观察结果将使我能够确定AD病理学的敏感性和获得的程度改变了应力轴功能。其次，我将在模拟动物的模型中应用压力源，并确定这如何改变与AD相关病理的度量，例如淀粉样蛋白斑块形成，神经原纤维样缠结样病理学和神经元变性。在第三个目标中，我将在遗传和药理上烧蚀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。该提案中描述的实验借鉴了我对果蝇和小鼠遗传学的经验以及我在压力神经内分泌学领域的工作。该提案的资金将使我能够在阿尔茨海默氏病研究领域获得新的培训，并获得AD神经病理学分析和行为特征方面的技能。综上所述，该建议描述了一项培训和研究计划，该计划将指导我的职业发展到一个新的水平，并让我在建立有关AD压力生物学的研究计划的同时顺利过渡到独立的研究职位。 公共卫生相关性：该项目将研究增加的压力是否导致阿尔茨海默氏病，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氏病的新疗法，并更好地了解如何在治疗阿尔茨海默氏病治疗当前可用的压力降低药物方面。