The role of central IGF- 1 feedback in the regulation of growth and metabolism

描述(申请人提供)：胰岛素样生长因子1(IGF-1)在生长激素(GH)表达和释放的负调控中的作用已通过体外和体内模型得到证实，但IGF-1的作用靶点和机制尚不清楚。我们开发了一种细胞特异性基因敲除小鼠，其中IGF-1受体(IGF-1R)从小鼠生长激素细胞中去除，以验证和表征IGF-1负调控；我们称之为生长抑素IGF-1R基因敲除小鼠(SIGFRKO)。SIGFRKO小鼠表现出GH基因表达和分泌增加，以及血清IGF-1增加。下丘脑生长激素释放激素水平降低，生长抑素mRNA表达水平升高，出现代偿性变化。SIGFRKO小鼠具有正常的线性生长，但到14周时体重显著低于对照组动物。此外，代谢研究表明，SIGFRKO小鼠的脂肪质量和身体脂肪百分比显著减少。为了进一步研究IGF-1对GH基因表达和分泌的负调控作用，我们已经开始建立基于体外细胞培养的模型。该项目的总体目标是进一步确定SIGFRKO小鼠的变化特征，并进行体外和体内研究，以描绘GH和IGF-1如何介导生长和新陈代谢的中枢控制。该项目将由克里斯托弗·罗梅罗博士在约翰·霍普金斯大学儿科内分泌学部的萨利·拉多维克博士的指导下进行。罗梅罗博士是一名儿科内分泌学家，他致力于利用基础和翻译研究的技能和知识来研究正常和异常生长的调节，以推进他在学术医学领域的职业生涯。拉多维克博士对与异常脑下垂体发育相关的人类生长障碍的长期研究兴趣以及她的指导经验将为罗梅罗博士提供必要的培训，以开启他作为独立调查员的职业生涯。儿科内分泌科、儿科新陈代谢学部、巴尔的摩糖尿病研究和培训中心以及大约翰霍普金斯大学的现有资源和协作研究人员将提供丰富的学习环境。此外，儿科系完全支持罗梅罗博士的学术进步。因此，罗梅罗博士开发的SIGFRKO模型系统，将为他提供新的体外和体内工具以进一步了解中央生长轴的重点研究，以及他在支持性环境中发展学术事业的决心，都是这位候选人未来成功的预测因素。此外，这些研究还将提高我们对正常和异常生长的生理学以及生长因子在调节新陈代谢中的作用的理解。 公共卫生相关性：目前对生长激素或胰岛素样生长因子-1缺乏症的诊断是基于临床表型和生化测试，这可能是可变的和不一致的。因此，关于合适的患者和治疗时间、应该使用哪种药物(GH与IGF-1)以及何时停止治疗的争议以及与使用促生长药物相关的安全问题继续存在。本提案中的研究将提供对生长和新陈代谢控制的更多了解，并可能有助于回答有关适当诊断和治疗的问题。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: 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.