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

描述（由申请人提供）：我是一名早期职业临床科学家，对衰老和阿尔茨海默病（AD）中下丘脑功能和全身代谢变化的基础和转化研究感兴趣，我正在申请Paul B. Beeson衰老临床科学家发展奖。该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的研究专业知识，(b)流行病学研究设计的专业知识，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我的长期职业目标，成为一名独立的临床医生-科学家在神经系统疾病领域的老化。我提议验证一个中心假设，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。这一中心假设将在三个具体目标中进行研究。Aim 1将使用大脑淀粉样蛋白-ß水平升高的小鼠模型（淀粉样蛋白-ß是阿尔茨海默病的关键致病因子）来验证过量的淀粉样蛋白-ß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。Aim 2将使用无偏分子谱分析方法，与正常对照相比，确定受asas影响的下丘脑细胞类型和信号通路，并确定恢复已确定的靶点是否能改善小鼠模型中的功能障碍。Aim 3将使用一组认知正常的受试者，无论是否有AD生物标志物阳性，来验证与正常衰老相比，临床前AD中瘦素信号素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，我组建了一个指导团队，包括康斯坦蒂诺·伊迪亚科拉博士（主要导师），威尔康奈尔医学院大脑和精神研究所主任，洛克菲勒大学HHMI调查员杰弗里·弗里德曼博士（联合导师），以及理查德·梅厄克斯博士（联合导师），哥伦比亚大学神经病学主任。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的进步。这项提议的研究意义重大，因为它填补了衰老和AD代谢功能障碍方面的明显知识空白，这是美国国家衰老研究所（National Institute of aging）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。比森奖将是我职业生涯中决定性的一步，因为它将使我获得专业培训和研究经验，成为这个研究领域中独立的临床科学家。

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.