The role of Leptin in Alzheimer's disease

描述（由申请人提供）：本提案描述了爱德华博士B的5年职业发展计划。李作为一个成功的独立的物理学家，科学家过渡。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促进一个合作研究项目。这个项目将为李博士提供极好的培训，使他成为一名独立的医生和科学家。该项目将指导博士雷克斯福德S。糖尿病、肥胖症和代谢研究所的Ahima博士和John Q. Trojanowski说，阿尔茨海默病核心中心和老龄化研究所的主任。这笔赠款将提供受保护的时间，使李博士将获得专业知识，在新陈代谢研究与正式的课程和众多的科学研讨会和会议。宾夕法尼亚大学的环境提供了独特的机会，可以利用其在衰老，代谢紊乱和神经退行性疾病方面的专业知识来进行拟议的项目，并为李博士提供成功的学术生涯所需的培训。 老龄化和肥胖都在影响美国人口的创纪录水平，老龄化和肥胖都是阿尔茨海默病（AD）的危险因素。尽管已知中年肥胖会增加AD的风险，并且饮食诱导的肥胖会促进转基因小鼠模型中的淀粉样蛋白沉积，但对肥胖如何对衰老的大脑产生不利影响的机制几乎没有了解。瘦素是一种由脂肪组织分泌的激素，通过作用于大脑而对新陈代谢产生深远的影响。瘦素水平由于衰老和肥胖而增加，这两种情况都会导致中枢瘦素抵抗。在转基因小鼠模型中，瘦素抑制大脑淀粉样蛋白，但我们对这种作用的理解受到阻碍，部分原因是瘦素既对神经元信号通路有直接影响，又对代谢有间接影响。 该建议的假设是，瘦素触发神经元信号通路，从而保护大脑淀粉样病变。瘦素的直接作用在瘦素缺乏的小鼠模型中难以确定，这是由于许多次级代谢作用，其使解释复杂化，包括肥胖、糖尿病、高脂血症和神经内分泌功能障碍。为了解决这个问题，李博士将进行创新的研究，以确定瘦素的影响控制体重的主要变化。发展脑淀粉样蛋白的转基因小鼠将用控制体重变化的生理剂量的瘦素治疗。其次，将在活体动物中评估急性瘦素治疗对下游信号传导途径和A2淀粉样肽水平的影响。最后，将确定增强瘦素受体信号传导的瘦素受体突变的行为和病理影响。这些研究将为瘦素在AD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.