Pathobiology of Hypothalamic and Metabolic Dysfunction in Normal Aging and Alzheimer's Disease

正常衰老和阿尔茨海默病中下丘脑和代谢功能障碍的病理学

• 批准号: 9138966
• 负责人: Makoto Ishii
• 金额: $ 17.28万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-15 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9138966
• 关键词: Adipocytes; Advisory Committees; Affect; Aging; Alzheimer' s Disease; Alzheimer' s disease risk; American; Amyloid; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Area; Award; Basic Science; Biological Assay; Biological Markers; Body Weight; Body Weight decreased; Brain; Cell Nucleus; Clinical; Clinical Skills; Cognitive deficits; Data; Dementia; Development; Diagnostic; Disease; Elderly; Ensure; Epidemiologic Studies; Epidemiology; Evolution; Fill-It; Functional disorder; Gerontology; Goals; Health; Hormones; Human; Human body; Hypothalamic dysfunction; Hypothalamic structure; Immunotherapy; Impaired cognition; Institutes; Knowledge; Lead; Leptin; Link; Longitudinal Studies; Mentors; Mentorship; Metabolic; Metabolism; Methods; Mind-Body Method; Molecular; Molecular Genetics; Molecular Profiling; Molecular Target; Mus; Neurodegenerative Disorders; Neurology; Neurons; Obesity; Outcome Study; Pathogenesis; Pathway interactions; Plasma; Play; Process; Psyche structure; Public Health; Research; Research Design; Research Institute; Research Personnel; Research Training; Rest; Role; Scientist; Senile Plaques; Signal Pathway; Signal Transduction; Staging; Structure of nucleus infundibularis hypothalami; Swedish mutation; Testing; Tg2576; Thalamic structure; Therapeutic; Time; Training; Transgenic Mice; Translational Research; United States; Universities; Washington; Well in self; Work; age related; aging population; amyloid pathology; base; bench to bedside; biomarker development; brain research; career; cell type; cognitive function; cohort; effective therapy; experience; innovation; insight; interest; medical schools; mouse model; nervous system disorder; neurophysiology; normal aging; novel; novel marker; novel therapeutics; overexpression; patch clamp; pre-clinical; preclinical study; programs; research study; response; restoration; skills; tool; trial design; validation studies

 DESCRIPTION (provided by applicant): I am an early career clinician-scientist interested in basic and translational research on the alterations in hypo- thalamic function and systemic metabolism occurring in aging and Alzheimer's disease (AD), and I am applying for the Paul B. Beeson Clinical Scientist Development Award in Aging. This award will provide me with the protected time for additional training needed to develop: (a) research expertise in normal aging and aging-related neurodegenerative disorders, (b) expertise in epidemiological study design, and (c) clinical skills in aging-related neurological disorders. These skills will help me fulfill y long-term career goal to become an independent clinician-scientist in the field of neurological disorders of aging. I propose to test the central hypothesis that alterations in leptin signaling i specific hypothalamic neurons is a key factor in the metabolic dysfunction and weight loss observed in the preclinical stages of AD, compared to normal aging. This central hypothesis will be investigated in three specific aims. Aim 1 will use mouse models with increased brain levels of amyloid- (A), a key pathogenic factor in AD, to test the hypothesis that excess A direcly disrupts hypothalamic signaling, and to compare the resulting dysfunction to normal age-matched function. Aim 2 will use an unbiased molecular profiling assay to identify the hypothalamic cell types and signaling pathways that are affected by A compared to normal controls, and determine if restoration of identified targets ameliorates the dysfunction in mouse models. Aim 3 will use a well-characterized cohort of cognitively normal subjects, with or without biomarker positivity for AD, to test the hypothesis that significant alterations in leptin signalin occur in preclinical AD compared to normal aging, and to elucidate their evolution as the cognitive impairment develops. To pursue these training and research objectives, I have assembled a mentoring team including Dr. Costantino Iadecola (primary mentor), Director, Brain and Mind Research Institute, Weill Cornell Medical College, Dr. Jeffrey Friedman (co-mentor), HHMI Investigator, Rockefeller University, and Dr. Richard Mayeux (co-mentor), Chair of Neurology, Columbia University. In addition, an advisory committee comprised of academic leaders in neurology, gerontology, epidemiology, and AD will ensure my progress in all training and research areas. The proposed research is significant because it fills an obvious knowledge gap in the metabolic dysfunction of aging and AD, a priority area for the National Institute of Aging, and may lead to novel therapies and biomarker development based on leptin signaling. Furthermore, the proposed research is innovative because it uses newly developed genetic and molecular approaches to elucidate novel aspects of the molecular and cellular bases of aging and AD-related disruption of systemic metabolism and other hypothalamic functions. The Beeson award will be a defining step in my career, as it will allow me to gain the specialized training and research experience needed to become an independent clinician-scientist in this understudied area of research.

 简介(申请人提供)：我是一名早期临床医生兼科学家，对衰老和阿尔茨海默病(AD)中下丘脑功能和系统新陈代谢的改变感兴趣，正在申请保罗·B·比森老年临床科学家发展奖。这一奖项将为我提供额外培训所需的保护时间，以发展：(A)正常衰老和与衰老相关的神经退行性疾病方面的研究专业知识，(B)流行病学研究设计方面的专业知识，以及(C)与衰老相关的神经疾病的临床技能。这些技能将帮助我实现长期的职业目标，成为一名在老年神经疾病领域的独立临床医生和科学家。我建议测试中心假设，与正常衰老相比，瘦素信号I特异性下丘脑神经元的变化是阿尔茨海默病临床前阶段观察到的代谢功能障碍和体重减轻的关键因素。这一中心假设将从三个具体目标进行研究。目的1将使用大脑淀粉样蛋白(A)水平升高的小鼠模型来验证A过量直接扰乱下丘脑信号的假说，并将由此产生的功能障碍与正常年龄匹配的功能进行比较。AIM 2将使用一种无偏倚的分子图谱分析来识别与正常对照相比受A影响的下丘脑细胞类型和信号通路，并确定已识别的靶点的恢复是否改善了小鼠模型的功能障碍。目的3将使用一组特征良好的认知正常受试者，无论有或没有AD生物标志物阳性，来检验与正常衰老相比，临床前AD患者瘦素信号发生显著变化的假设，并阐明它们随着认知障碍的发展而演变。为了实现这些培训和研究目标，我组建了一个导师团队，成员包括威尔·康奈尔医学院脑与智力研究所所长Costantino Iadecola博士(首席导师)、洛克菲勒大学HHMI研究员Jeffrey Friedman博士(共同导师)和哥伦比亚大学神经病学主席Richard Mayeux博士(共同导师)。此外，一个由神经学、老年学、流行病学和AD领域的学术领袖组成的咨询委员会将确保我在所有培训和研究领域取得进展。这项拟议的研究具有重要意义，因为它填补了衰老和AD代谢功能障碍方面的一个明显的知识空白，这是美国国家老龄研究所的优先领域，并可能导致基于瘦素信号的新疗法和生物标记物的开发。此外，这项拟议的研究具有创新性，因为它使用了新开发的遗传学和分子方法来阐明衰老的分子和细胞基础以及与AD相关的系统代谢和其他下丘脑功能障碍的新方面。Beeson奖将是我职业生涯中决定性的一步，因为它将使我获得所需的专业培训和研究经验，以成为这一研究不足领域的独立临床医生兼科学家。