Early Onset Obesity and Cognitive Impairment in Pseudohypoparathyroidism

描述(由申请者提供)：本申请的主要目标是提供一个全面的培训计划，为我独立资助的专注于下丘脑肥胖的病理生理学和治疗的翻译研究生涯做好准备。我是儿科内分泌科和糖尿病科的儿科讲师，拥有以患者为中心的研究高级学位(临床调查理学硕士)。我的近期目标是加强我对下丘脑控制能量平衡的理解，进一步提高我的临床研究技能，并获得动物模型方面的专业知识。这个奖项将允许我通过正式的研究生水平的课程工作、关于使用动物模型的研讨会和有指导的研究的受保护时间来实现我的目标。我的主要导师罗杰·科恩博士是一位国际知名的科学家，在能量稳态的中央控制方面拥有专业知识，我的共同导师威廉·罗素博士是一位经验丰富的临床医生和临床研究人员。我的两位导师都有指导年轻科学家的长期记录，自从我2009年来到范德比尔特以来，他们一直在指导我。范德比尔特大学医学中心为研究和年轻研究人员的培训提供了一个特殊的环境，可以使用CTSA资源和众多核心实验室设施。这项研究应用扩展了我之前发表的关于减少能量消耗在假性甲状旁腺功能减退症1a型(PHP1a)儿童早发性肥胖中的作用的工作。PHP1a是一种遗传性疾病，会导致早发性、综合征性肥胖。虽然PHP1a是一种罕见的疾病，但我对这一人群的研究可以扩展到其他形式的下丘脑肥胖症，并可能通过提高我们对能量平衡的中央控制的理解，为我们对常见肥胖症的管理提供信息。这项应用将调查PHP1a儿童热量摄入过多的机制。一篇新兴的文献强调了肥胖和认知障碍之间的相互作用。我们假设患有PHP1a的儿童有认知障碍，特别是执行功能差，这是通过增加蔗糖偏好和基于奖励的决策而导致超重增加的。我们将进行一项临床研究，以评估PHP1a儿童的认知障碍程度，重点是执行功能。我们将使用有效的测量方法评估食物摄入量、饮食行为和蔗糖偏好。这项研究将为未来治疗PHP1a和其他肥胖综合征儿童异常体重增加的临床试验提供信息。为了补充这项临床研究，我们将确定PHP1a的小鼠模型是否是该疾病中出现的进食行为和认知障碍的合适模型。如果动物模型概括了人类的表型，我们将提出未来的研究，以探索中枢神经系统受体信号在PHP1a中的具体变化。

DESCRIPTION (provided by applicant): The overarching goal of this application is to provide a comprehensive training program to prepare me for an independently funded translational research career focused on the pathophysiology and treatment of hypothalamic obesity. I am an Instructor of Pediatrics in the Division of Pediatric Endocrinology and Diabetes with an advanced degree in patient-oriented research (Master of Science in Clinical Investigation). My near term goal is to is to strengthen my understanding of hypothalamic control of energy balance, further my clinical investigation skills and to gain expertise in animal models. This award will allow me to achieve my goal through formal graduate-level coursework, workshops on the use of animal models and protected time for mentored research. My primary mentor, Dr. Roger Cone, is an internationally renowned scientist with expertise in central control of energy homeostasis and my co-mentor, Dr. William Russell, is an experienced clinician and clinical researcher. Both of my mentors have a long track record of mentoring young scientists and have mentored me since my arrival at Vanderbilt in 2009. Vanderbilt University Medical Center provides an exceptional environment for research and the training of young investigators with access to CTSA resources and numerous Core laboratory facilities. This research application extends my prior published work on the role of reduced energy expenditure in early-onset obesity in children with pseudohypoparathyroidism type 1a (PHP1a). PHP1a is a genetic disorder that causes early-onset, syndromic obesity. While PHP1a is a rare disorder, my work with this population can be extended to other forms of hypothalamic obesity and may inform our management of common obesity by improving our understanding of the central control of energy balance. This application will investigate the mechanisms underlying excess caloric intake in children with PHP1a. An emerging body of literature highlights the interplay between obesity and cognitive impairment. We hypothesize that children with PHP1a have cognitive impairment, specifically poor executive function, which contributes to excess weight gain through increased sucrose preference and reward-based decision making. We will conduct a clinical study to evaluate the degree of cognitive impairment in children with PHP1a with a focus on executive function. We will evaluate food intake, eating behaviors and sucrose preference using validated measures. This study will inform future clinical trials for treatment of abnormal weight gain in children with PHP1a and other obesity syndromes. To supplement this clinical study, we will determine if the mouse model of PHP1a is an appropriate model of the eating behaviors and cognitive impairment seen in the disorder. If the animal model recapitulates the human phenotype we will propose future studies to explore specific alterations in central nervous system receptor signaling in PHP1a.