The role of insulin-like growth factor 1 (IGF-1) in the negative regulation of growth hormone (GH) expression and release is demonstrated by in vitro and in vivo models;however, the targets and mechanisms of IGF-1 action remain unclear. We have developed a cell-specific knockout mouse in which the IGF-1 receptor (IGF- 1R) was ablated from the mouse somatotroph in order to validate and characterize IGF-1 negative regulation;we termed this the somatotroph IGF-1R knockout (SIGFRKO) mouse. SIGFRKO mice demonstrated increased GH gene expression and secretion as well as increased serum IGF-1. Compensatory changes were noted with decreased growth hormone releasing hormone and increased somatostatin mRNA expression levels in the hypothalamus. SIGFRKO mice had normal linear growth, but by 14 weeks of age weighed significantly less than control animals. Furthermore, metabolic studies revealed SIGFRKO mice had significantly less fat mass and body percent fat. To further characterize IGF-1 negative regulation of GH gene expression and secretion, we have begun to develop an in vitro cell culture based model. The overall goal of this project is to characterize further the alterations in the SIGFRKO mouse and perform in vitro and in vivo studies to delineate how GH and IGF-1 mediate central control of growth and metabolism. This project will be conducted by Dr. Christopher Romero under the guidance of Dr. Sally Radovick in the Division of Pediatric Endocrinology at Johns Hopkins University. Dr. Romero, a Pediatric Endocrinologist, is dedicated to advancing his career in academic medicine using skills and knowledge of basic and translational research to study the regulation of normal and abnormal growth. Dr. Radovick's long-standing research interests in human growth disorders associated with abnormal pituitary development and her mentoring experience will provide Dr. Romero with the training necessary to initiate his career as an independent investigator. The available resources and the collaborating research faculty within the Divisions of Pediatric Endocrinology, Pediatric Metabolism, the Baltimore Diabetes Research and Training Center and the greater Johns Hopkins University will provide a rich learning environment. Furthermore, The Department of Pediatrics is completely supportive of the academic advancement of Dr. Romero. Thus, the SIGFRKO model system developed by Dr. Romero, the focused studies that will provide him with novel in vitro and in vivo tools to gain further understanding of the central growth axis and his determination to develop his academic career within a supportive environment are all predictors of future success for this candidate. These studies, moreover, will improve our understanding of the physiology of both normal and abnormal growth and the role of growth factors in regulating metabolism.
The current diagnosis of GH or IGF-1 deficiency is based on clinical phenotyping and biochemical testing that may be variable and inconsistent. Thus, controversies regarding the appropriate patients to treat and length of treatment, which drug (GH vs. IGF-1) should be used and when to stop treatment, continue along with the safety issues associated with administration of growth promoting agents. The studies in this proposal will provide a greater understanding of the control of growth and metabolism and may help answer questions regarding appropriate diagnosis and treatment.