Early Onset Obesity and Cognitive Impairment in Pseudohypoparathyroidism

假性甲状旁腺功能减退症的早发性肥胖和认知障碍

• 批准号: 9261103
• 负责人: Ashley Hall Shoemaker
• 金额: $ 5.25万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9261103
• 关键词: Early; Onset; Obesity; Cognitive; Impairment

DESCRIPTION (provided by applicant): The overarching goal of this proposal 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 in order t equip myself as an independent, translational researcher. 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 scientist 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 proposal 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 proposal 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 the development of a future lifestyle intervention to modify the rate of 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.

描述（由申请人提供）：本提案的总体目标是为我提供一个全面的培训计划，为我独立资助的下丘脑肥胖病理生理学和治疗的转化研究事业做好准备。我是儿科内分泌和糖尿病科的儿科讲师，拥有患者导向研究的高级学位（临床研究理学硕士）。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，以使自己成为一名独立的转化研究者。这个奖项将允许我通过正式的研究生课程，关于动物模型使用的研讨会和受指导的研究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·拉塞尔博士是一位经验丰富的临床医生和临床研究员。我的两位导师都有指导年轻科学家的长期记录，自从我2009年来到范德比尔特大学以来，他们一直在指导我。范德比尔特大学医学中心为年轻研究人员的研究和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。这项研究计划扩展了我之前发表的关于减少能量消耗在1a型假性甲状旁腺功能低下（PHP1a）儿童早发性肥胖中的作用的研究。PHP1a是一种遗传性疾病，可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，并可能通过提高我们对能量平衡中枢控制的理解，为我们管理普通肥胖提供信息。本研究将探讨PHP1a患儿热量摄入过多的机制。越来越多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，这有助于通过增加对蔗糖的偏好和基于奖励的决策来增加体重。我们将开展一项临床研究，评估PHP1a患儿的认知障碍程度，重点关注执行功能。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。这项研究将为未来生活方式干预的发展提供信息，以改变患有PHP1a和其他肥胖综合征的儿童的体重增加率。为了补充这项临床研究，我们将确定PHP1a小鼠模型是否是该疾病饮食行为和认知障碍的合适模型。如果动物模型再现了人类表型，我们将提出未来的研究来探索中枢神经系统受体信号在PHP1a中的特异性改变。