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.
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.
|Chia, Dennis J (2014) Minireview: mechanisms of growth hormone-mediated gene regulation. Mol Endocrinol 28:1012-25|
|Santhanam, Mahalakshmi; Chia, Dennis J (2013) Hepatic-specific accessibility of Igf1 gene enhancers is independent of growth hormone signaling. Mol Endocrinol 27:2080-92|