Epigenetic Actions of Growth Hormone

描述（由申请人提供）：拟议的项目扩展了医师-科学家职业发展奖（K08），重点研究生长激素（GH）调节胰岛素样生长因子- i （IGF-I）基因转录的机制。具有儿科内分泌学的临床背景，研究者在健康相关研究领域的广泛目标集中在理解细胞内信号通路和基因调控中激素的整合。由于igf - 1与包括癌症和糖尿病在内的许多慢性和代价高昂的疾病有关，因此对igf - 1的研究对公共卫生具有重大意义。先前的研究表明，igf1基因位点的关键调控元件携带激活基因的特征，即使在没有急性生长激素信号传导的情况下，这表明表观遗传机制在GH - IGF-I轴的调控中发挥了重要作用。该项目的目的是：(1)建立可重复的小鼠模型来研究GH的信号转导和基因调控；(2)表征igf1基因染色质可及性的动态变化。标准的分子生物学技术，包括染色质免疫沉淀（ChIP）测定和衍生物甲醛辅助分离调控元件（FAIRE），将用于从小鼠肝脏制备的样品，在全身生长激素治疗前后。长效生长抑素类似物奥曲肽将用于抑制内源性生长激素的分泌。该提案的实验将为未来的研究项目提供关键的实验工具和初步数据，这些项目将完成向完全独立研究者地位的过渡。

DESCRIPTION (provided by applicant): The proposed project extends from a Physician-Scientist Career Development Award (K08) that focuses on the mechanisms by which growth hormone (GH) regulates transcription of the Insulin-like growth factor-I (IGF-I) gene. With a clinical background in pediatric endocrinology, the broad objectives of the investigator's career in health-related research are centered on understanding the integration of hormones on intracellular signaling pathways and gene regulation. The study of IGF-I is of significant interest to the public health given its links to many chronic and costly diseases, including cancer and diabetes. Previous studies have revealed that key regulatory elements of the igf1 gene locus carry features of an activated gene, even in the absence of acute GH signaling, thereby suggesting a significant contribution of epigenetic mechanisms in the regulation of the GH - IGF-I axis. The aims of the project are to (1) establish a reproducible mouse model to study signal transduction and gene regulation by GH, and (2) characterize dynamic changes in chromatin accessibility of the igf1 gene. Standard molecular biology techniques, including chromatin immunoprecipitation (ChIP) assay and the derivative formaldehyde-assisted isolation of regulatory elements (FAIRE), will be employed on samples prepared from the livers of mice before and after systemic GH treatment. The long-acting somatostatin analog, octreotide, will be utilized to suppress endogenous GH secretion. The experiments of the proposal will provide key experimental tools and preliminary data for future research projects that will complete the transition to fully independent investigator status.