Epigenetic Actions of Growth Hormone

描述(由申请人提供)：拟议的项目扩展自医生-科学家职业发展奖(K08)，重点是生长激素(GH)调节胰岛素样生长因子-I(IGF-I)基因转录的机制。拥有儿科内分泌学的临床背景，这位研究员在健康相关研究的职业生涯中的广泛目标是了解激素在细胞内信号通路和基因调控中的整合。IGF-I的研究对公共卫生具有重大意义，因为它与许多慢性和代价高昂的疾病有关，包括癌症和糖尿病。以往的研究表明，IGF1基因座的关键调控元件具有激活基因的特征，即使在没有急性GH信号的情况下也是如此，因此表明表观遗传机制在GH-IGF-I轴的调节中具有重要作用。该项目的目的是(1)建立一个可复制的小鼠模型，研究GH对信号转导和基因调控的作用；(2)研究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)和衍生的甲醛辅助的调节元件分离(FAIRE)，将被应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调查者身份的过渡。 公共卫生相关性：胰岛素样生长因子-I(IGF-I)是一种在人类健康和疾病状态中发挥重要作用的蛋白质。这个项目研究的过程改变了编码这种蛋白质的遗传物质的阅读方式，从而影响了体内存在多少蛋白质的作用。

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. PUBLIC HEALTH RELEVANCE: Insulin-like growth factor-I (IGF-I) is a protein that has important roles in human health and disease states. This project investigates processes that change how the genetic material encoding this protein is read and therefore impact how much of the protein is present to act in the body.