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

中枢IGF-1反馈在生长和代谢调节中的作用

• 批准号: 8110929
• 负责人: Christopher Joseph Romero
• 金额: $ 15.87万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8110929
• 关键词: Address; Age; Anatomy; Attenuated; Baltimore; Basic Science; Biochemical; Biological Models; Cell Culture Techniques; Cell Line; Cells; Childhood; Control Animal; Critical Pathways; Data; Deposition; Diabetes Mellitus; Diagnosis; Endocrinologist; Endocrinology; Environment; Faculty; Fatty acid glycerol esters; Feedback; Figs - dietary; Future; Gene Expression; Goals; Growth; Growth Disorders; Growth Factor; Hormones; Human; Hypothalamic structure; In Vitro; Insulin-Like Growth Factor I; Insulin-Like-Growth Factor I Receptor; Investigation; Knock-out; Knockout Mice; Knowledge; Learning; Length; Mediating; Medicine; Mentors; Metabolic; Metabolic Marker; Metabolism; Modeling; Mus; Neurons; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Physiology; Pituitary Gland; Play; Rattus; Receptor Signaling; Regulation; Regulatory Pathway; Research; Research Personnel; Research Training; Resources; Role; Safety; Serum; Signal Transduction; Somatostatin; Somatotropin; Somatotropin-Releasing Hormone; System; Testing; Training; Translational Research; Universities; Weight Gain; Work; base; career; cellular targeting; clinical phenotype; experience; hormone regulation; improved; in vivo; in vivo Model; interest; mRNA Expression; metabolic abnormality assessment; mouse model; novel; pediatric department; pituitary gland development; receptor; skills; success; tool

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.

性状（由申请方提供）：体外和体内模型证明了胰岛素样生长因子1（IGF-1）在生长激素（GH）表达和释放负调控中的作用;然而，IGF-1作用的靶点和机制仍不清楚。我们已经开发了一种细胞特异性敲除小鼠，其中IGF-1受体（IGF-1 R）从小鼠生长激素细胞中被切除，以验证和表征IGF-1负调控;我们将其称为生长激素细胞IGF-1 R敲除（SIGFRKO）小鼠。SIGFRKO小鼠表现出GH基因表达和分泌增加以及血清IGF-1增加。下丘脑中生长激素释放激素减少和生长抑素mRNA表达水平增加，注意到代偿性变化。SIGFRKO小鼠具有正常的线性生长，但到14周龄时，体重明显低于对照动物。此外，代谢研究显示，SIGFRKO小鼠的脂肪量和身体脂肪百分比显著降低。为了进一步表征IGF-1对GH基因表达和分泌的负调控，我们已经开始开发基于体外细胞培养的模型。该项目的总体目标是进一步表征SIGFRKO小鼠的变化，并进行体外和体内研究，以描述GH和IGF-1如何介导生长和代谢的中枢控制。该项目将由约翰霍普金斯大学儿科内分泌科的Christopher Romero博士在Sally Radovick博士的指导下进行。罗梅罗，儿科内分泌学家，致力于推进他的职业生涯在学术医学使用的技能和知识的基础和转化研究，研究正常和异常生长的调节。Radovick博士对与垂体发育异常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Romero博士提供开始独立研究者职业生涯所需的培训。现有的资源和儿科内分泌学，儿科代谢，巴尔的摩糖尿病研究和培训中心和更大的约翰霍普金斯大学的部门内的合作研究人员将提供一个丰富的学习环境。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，重点研究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，以及他在支持性环境中发展学术生涯的决心，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代谢中的作用的理解。 公共卫生相关性：目前GH或IGF-1缺乏症的诊断是基于临床表型和生化检测，可能是可变的和不一致的。因此，关于治疗的适当患者和治疗时间长度、应使用哪种药物（GH vs. IGF-1）以及何时停止治疗的争议继续沿着与给予生长促进剂相关的安全性问题。本提案中的研究将提供对生长和代谢控制的更好理解，并可能有助于回答有关适当诊断和治疗的问题。