The role of Leptin in Alzheimer's disease

描述（由申请人提供）：此提案描述了Edward B. Lee博士的5年职业发展计划，以过渡到成功的独立医师-科学家。李博士在宾夕法尼亚大学完成了解剖病理学和神经病理学的临床培训，现在将与内分泌学和神经病理学的资源一起开展合作研究项目。这个项目将为李博士发展成为一名独立的内科科学家提供极好的训练。该项目将由糖尿病、肥胖和代谢研究所的Rexford S. Ahima博士指导，并由阿尔茨海默病核心中心和衰老研究所主任John Q. Trojanowski博士共同指导。这项资助将提供受保护的时间，以便李博士通过正式课程和众多科学研讨会和会议获得代谢研究方面的专业知识。宾夕法尼亚大学的环境提供了独特的机会，可以发挥其在衰老，代谢紊乱和神经退行性疾病方面的专业知识来开展拟议的项目，并为李博士提供迈向成功学术生涯所需的培训。老龄化和肥胖对美国人口的影响都达到了创纪录的水平，而老龄化和肥胖都是阿尔茨海默病（AD）的危险因素。虽然，我们知道中年肥胖会增加AD的风险，并且在转基因小鼠模型中，饮食诱导的肥胖会促进淀粉样蛋白沉积，但关于肥胖如何对衰老的大脑产生不利影响的机制知之甚少。瘦素是一种由脂肪组织分泌的激素，通过作用于大脑对新陈代谢有深远的影响。由于衰老和肥胖，瘦素水平升高，这两种情况都会导致中枢性瘦素抵抗。瘦素在转基因小鼠模型中抑制大脑淀粉样蛋白，但我们对这种作用的理解受到阻碍，部分原因是瘦素对神经元信号通路有直接影响，对代谢有间接影响。这一提议的假设是瘦素触发神经元信号通路，防止大脑淀粉样蛋白病理。由于肥胖、糖尿病、高脂血症和神经内分泌功能障碍等多种继发代谢影响，瘦素在小鼠瘦素缺乏模型中的直接作用难以确定。为了避免这个问题，李博士将进行创新研究，以确定瘦素对控制体重主要变化的作用。产生脑淀粉样蛋白的转基因小鼠将接受生理剂量的瘦素治疗，以控制体重变化。其次，急性瘦素治疗对下游信号通路和A2淀粉样肽水平的影响将在活体动物中进行评估。最后，将确定瘦素受体突变增强瘦素受体信号传导的行为和病理效应。这些研究将为瘦素在阿尔茨海默病发病机制中的作用提供机制见解，并为未来药物或生物标志物的开发提供基础。

DESCRIPTION (provided by applicant): This proposal describes a 5 year career development plan for Dr. Edward B. Lee to serve as a transition to successful independent physician-scientist. Dr. Lee has completed his clinical training in Anatomic Pathology and Neuropathology at the University of Pennsylvania, and will now foster a collaborative research project with the resources of both Endocrinology and Neuropathology. This project will provide superb training for Dr. Lee to develop into an independent physician-scientist. The project will be mentored Dr. Rexford S. Ahima of the Institute for Diabetes, Obesity and Metabolism, and co-mentored by Dr. John Q. Trojanowski, Director of the Alzheimer's Disease Core Center and the Institute on Aging. This grant will provide the protected time so that Dr. Lee will gain expertise in metabolism research with formal coursework and numerous scientific seminars and meetings. The environment at the University of Pennsylvania provides the unique opportunity to parlay its expertise in aging, metabolic disorders and neurodegenerative diseases to conduct the proposed projects, and to provide Dr. Lee with the training required to proceed towards a successful academic career. Aging and obesity are both affecting the American population at record levels, and both aging and obesity are risk factors for Alzheimer's disease (AD). Although, it is known that mid-life obesity increases the risk of AD and that diet-induced obesity promotes amyloid deposition in transgenic mouse models, there is little mechanistic insight into how obesity adversely affects the aging brain. Leptin is a hormone secreted by adipose tissue with profound effects on metabolism by acting on the brain. Leptin levels are increased due to aging and obesity, and both conditions results in central leptin resistance. Leptin inhibits cerebral amyloid in transgenic mouse models, but our understanding of this effect is hampered in part because leptin has both direct effects on neuronal signaling pathways and indirect effects on metabolism. The hypothesis of this proposal is that leptin triggers neuronal signaling pathways which protect against cerebral amyloid pathology. The direct effects of leptin are difficult to ascertain in mouse models of leptin deficiency due to the numerous secondary metabolic effects which complicate interpretation including obesity, diabetes, hyperlipidemia and neuroendocrine dysfunction. To circumvent this issue, Dr. Lee will perform innovative studies to determine leptin's effects controlling for major shifts in body weight. Transgenic mice that develop cerebral amyloid will be treated with physiologic doses of leptin controlling for changes in body weight. Second, the effects of acute leptin treatment on downstream signaling pathways and A2 amyloid peptide levels will be assessed in live animals. Finally, the behavioral and pathologic effects of a leptin receptor mutation which enhances leptin receptor signaling will be determined. These studies will provide mechanistic insights into the role of leptin in AD pathogenesis, and provide the basis for future drug or biomarker development.