Metabolic hormones, aging, and Alzheimer's Disease

 描述(由申请人提供)：这一K99/R00奖项将是莫里斯博士职业计划发展过程中不可或缺的一部分，该计划旨在将她在神经退行性疾病和新陈代谢方面的博士前临床前培训扩展到人类受试者的研究。Morris博士在她的F32 NRSA项目中展示了她实现这一转变的能力，该项目使她能够在健康老年人、临床前阿尔茨海默病(AD)和AD受试者中实施高胰岛素-正常血糖钳夹程序，这是测量胰岛素抵抗的黄金标准。虽然莫里斯博士在过去两年中接受了临床研究方面的培训，但她还需要更多关于AD方法学(特别是神经成像)的高级培训，以及更多的代谢指标。虽然高胰岛素-正常血糖钳是为测量胰岛素抵抗而优化的，但它不测量激素分泌，该项目将允许莫里斯博士接受一种与生理相关的测量胰岛素分泌的方法--混合餐耐量试验的培训。此外，它将允许莫里斯博士进行翻译观察，将个体受试者的细胞生物能量学与临床生理学和 成像结果。莫里斯博士将在杰弗里·伯恩斯博士的指导下在堪萨斯大学医学中心(KUMC)的神经科工作。Morris博士将利用KUMC的几个研究优势：霍格伦德脑成像中心、NIH指定的阿尔茨海默病中心以及临床和翻译科学单位(由NIH CTSA资助)。拟议的额外培训将使她能够有效地比较健康老龄化和AD患者的代谢激素分泌，与大脑结构的关系，以及可能导致代谢失调的机制，包括遗传学和线粒体功能障碍。为了对代谢(特别是膳食诱导的胰腺和胃肠道分泌激素的分泌)在衰老和阿尔茨海默病中的作用提出更复杂的问题，她将需要额外的指导培训，包括生理学家John Thyerror博士指导的代谢分析、KUMC阿尔茨海默病中心主任、KUMC神经学教授Russell Swerdlow博士的细胞生物能量学以及Burns博士的成像测量(MRI)。资金雄厚、经验丰富的导师、教育和临床研究经验的结合为莫里斯博士的职业目标提供了一个理想的载体。莫里斯博士的总体目标是通过研究阿尔茨海默病患者胰岛素抵抗的具体机制，包括代谢激素分泌失调和生物能量障碍，在她之前的工作基础上再接再厉。我们将使用与生理上最相关的方法来测量胰腺功能，即混合餐耐量试验，它将允许同时测量胰岛细胞功能、胰岛素激素分泌和胰岛素抵抗。这些结果将与线粒体功能有关，并以包括大脑萎缩和认知轨迹在内的纵向衰退指标来表征。

 DESCRIPTION (provided by applicant): This K99/R00 award will be integral in the development of Dr. Morris' career plan, which was designed to extend her pre-doctoral preclinical training in neurodegenerative disease and metabolism to human subjects research. Dr. Morris has shown her ability to make this transition in her F32 NRSA project, which allowed her to implement the hyperinsulinemic-euglyecmic clamp procedure, the gold standard for measuring insulin resistance, in healthy elderly, preclinical Alzheimer's Disease (AD), and AD subjects. While Dr. Morris has received training in clinical research over the past 2 years, she needs additional advanced training in AD methodology (specifically neuroimaging), and additional metabolic measures. While the hyperinsulinemic- euglycemic clamp is optimized for measuring insulin resistance, it does not measure hormone secretion, and this project will allow Dr. Morris to obtain training in a physiologically-relevant method of measuring insulin secretion, the mixed meal tolerance test. Moreover, it will allow Dr. Morris to make translational observations, linking cellular bioenergetics in individual subjects with clinical physiological and imaging outcomes. Dr. Morris will work in the department of Neurology at the University of Kansas Medical Center (KUMC) under the mentorship of Dr. Jeffrey Burns. Dr. Morris will capitalize on several of KUMC's research strengths: the Hoglund Brain Imaging Center, the NIH-designated Alzheimer's Disease Center, and the Clinical and Translational Science Unit (funded through an NIH CTSA). The proposed additional training will allow her to effectively compare metabolic hormone secretion in healthy aging and AD, the relationship with brain structure, and mechanisms that could be driving metabolic dysregulation, including genetics and mitochondrial dysfunction. In order to ask more complex questions about the role of metabolism (specifically, meal induced secretion of pancreatic and GI secreted hormones) in aging and AD, she will need additional mentored training in metabolic analyses under physiologist Dr. John Thyfault, cellular bioenergetics under Dr. Russell Swerdlow, Director of the KU Alzheimer's Disease Center and Professor of Neurology at KUMC, and imaging measures (MRI) under Dr. Burns. The combination of well-funded and experienced mentors, education, and clinical research experience provides an ideal vehicle for advancing Dr. Morris' career goals. Dr. Morris' overall goal is to build upon her previous work by investigating specific mechanisms of insulin resistance in AD, including dysregulated metabolic hormone secretion and bioenergetic dysfunction. We will use the most physiologically-relevant method of measuring pancreatic function, the mixed meal tolerance test, which will allow simultaneous measurement of beta cell function, incretin hormone secretion, and insulin resistance. These results will be related to mitochondrial function and characterized in terms of longitudinal measures of decline, including brain atrophy and cognitive trajectory.