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: 8966084
• 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/8966084
• 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; Mutation; 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; 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; 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 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-ß (Aß), a key pathogenic factor in AD, to test the hypothesis that excess Aß 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 Aß 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.

描述（由申请人提供）：我是一名早期职业临床医生-科学家，对衰老和阿尔茨海默病（AD）中下丘脑功能和全身代谢改变的基础和转化研究感兴趣，我正在申请Paul B。Beeson老龄化临床科学家发展奖。该奖项将为我提供受保护的时间，以进行所需的额外培训，以发展：（a）正常衰老和衰老相关神经退行性疾病的研究专业知识，（B）流行病学研究设计的专业知识，以及（c）衰老相关神经系统疾病的临床技能。这些技能将帮助我实现我的长期职业目标，成为一名独立的临床科学家，在神经系统疾病的衰老领域。我建议测试中心的假设，瘦素信号i特定的下丘脑神经元的改变是一个关键因素，在临床前阶段的AD中观察到的代谢功能障碍和体重减轻，相比正常老化。这一中心假设将在三个具体目标进行研究。目的1将使用具有增加的脑淀粉样蛋白-β（A β）（AD中的关键致病因子）水平的小鼠模型来测试过量的A β直接破坏下丘脑信号传导的假设，并将所产生的功能障碍与正常年龄匹配的功能进行比较。目的2将使用无偏分子谱分析来鉴定与正常对照相比受Ablation影响的下丘脑细胞类型和信号传导途径，并确定鉴定的靶点的恢复是否改善小鼠模型中的功能障碍。目标3将使用认知正常受试者的良好表征的队列，具有或不具有AD的生物标志物阳性，以检验与正常老化相比在临床前AD中发生瘦素信号蛋白的显著改变的假设，并阐明其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，我组建了一个指导团队，包括威尔康奈尔医学院脑与思维研究所所长Costantino Iadecola博士（主要导师）、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的进步。这项研究意义重大，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，这是美国国家老龄化研究所的一个优先领域，并可能导致基于瘦素信号传导的新疗法和生物标志物的开发。此外，拟议的研究是创新的，因为它使用新开发的遗传和分子方法来阐明衰老和AD相关的全身代谢和其他下丘脑功能破坏的分子和细胞基础的新方面。Beeson奖将是我职业生涯中的决定性一步，因为它将使我获得成为这一未充分研究领域的独立临床科学家所需的专业培训和研究经验。