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: 9278060
• 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/9278060
• 关键词: Adipocytes; Advisory Committees; Affect; Age; 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; Cognitive deficits; Data; Dementia; Development; Diagnostic; Disease; Elderly; Ensure; Epidemiology; Evolution; Fill-It; Functional disorder; Genetic; Gerontology; Goals; 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 Profiling; Molecular Target; Mus; Neurodegenerative Disorders; Neurology; Neurons; Obesity; Outcome Study; Pathogenesis; Pathway interactions; Phenotype; Plasma; Play; Process; Psyche structure; Public Health; Research; Research Design; Research Institute; Research Personnel; Rest; Role; Scientist; Senile Plaques; Signal Pathway; Signal Transduction; Structure of nucleus infundibularis hypothalami; Swedish mutation; Testing; Tg2576; Therapeutic; Time; Training; Transgenic Mice; Translational Research; United States; Universities; Virulence Factors; Washington; Well in self; abeta accumulation; age related; aging population; amyloid pathology; base; bench to bedside; biomarker development; brain research; career; cell type; cognitive function; cohort; effective therapy; epidemiology study; experience; experimental study; innovation; insight; interest; medical schools; mouse model; nervous system disorder; neurophysiology; normal aging; novel; novel therapeutics; overexpression; patch clamp; peptide B; pre-clinical; preclinical study; public health relevance; response; restoration; skills; therapy development; tool; translational research program; 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.

 描述（由申请人提供）：我是一名早期职业临床医生兼科学家，对衰老和阿尔茨海默氏病 (AD) 中下丘脑功能和全身代谢变化的基础和转化研究感兴趣，我正在申请保罗·B·比森衰老临床科学家发展奖。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长期职业目标，成为衰老神经系统疾病领域的独立临床医生科学家。我建议检验一个中心假设，即与正常衰老相比，特定下丘脑神经元中瘦素信号传导的改变是 AD 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。我们将通过三个具体目标来研究这一中心假设。目标 1 将使用大脑中淀粉样蛋白- (A)（AD 的关键致病因素）水平升高的小鼠模型来检验过量的 A 会直接破坏下丘脑信号传导的假设，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。目标 2 将使用无偏倚的分子分析测定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，并确定恢复已识别靶点是否可以改善小鼠模型中的功能障碍。目标 3 将使用一组特征明确的认知正常受试者（无论有或没有 AD 生物标志物阳性）来检验以下假设：与正常衰老相比，临床前 AD 中瘦素信号蛋白发生显着变化，并阐明其随着认知障碍发展的演变。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大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系主任 Richard Mayeux 博士（共同导师）。此外，由神经病学、老年学、流行病学和 AD 领域的学术带头人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。拟议的研究意义重大，因为它填补了衰老和 AD 代谢功能障碍（国家衰老研究所的优先领域）方面的明显知识空白，并可能导致基于瘦素信号传导的新疗法和生物标志物开发。此外，拟议的研究具有创新性，因为它使用新开发的遗传和分子方法来阐明衰老的分子和细胞基础以及与 AD 相关的全身代谢和其他下丘脑功能破坏的新方面。比森奖将是我职业生涯中的决定性一步，因为它将让我获得成为这一研究领域的独立临床医生所需的专业培训和研究经验。