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.
Childhood obesity is a growing epidemic without effective treatment options. Currently, almost a third of children are overweight or obese and at high risk of obesity-related diseases such as type 2 diabetes, fatty liver and heart disease. This application aims to further our understanding of the genetic basis of childhood obesity, allowing for the development of more precisely targeted obesity treatments.