The goal of this research proposal is to gain a better understanding of the interaction between the hypothalamic- pituitary-thyroid axis and the somatostatinergic system and their combined effect of pituitary thyrotrope regulation. Using the murine TtT-97 thyrotropic tumor model, we have previously demonstrated that treatment with thyroid hormone reduces tumor size in association with enhanced expression of the mouse somatostatin receptor type 5 (msst5) gene. The studies proposed aim to characterize these in vivo observations by investigating basal promoter activity of the msst5 gene and its regulation by thyroid hormone. Not only will these data enhance our understanding of the basic molecular mechanisms of the somatostatinergic system and pituitary regulation, but have long range clinical applications regarding the pathogenesis and treatment of neuroendocrine tumors. The somatostatin analog, octreotide, has been used to treat a variety of neuroendocrine tumors and description of the molecular mechanisms of the somatostatinergic system will be of clinical application to these diseases. Further knowledge of somatostatin receptor function and regulation will potentially contribute to the development of more efficacious somatostatin analogs for the diagnosis and treatment of neuroendocrine tumors. The proposed research will take place in the Division of Endocrinology at the University of Colorado Health Sciences Center in Denver, CO under the direction of Division Chief Dr. E. C. Ridgway. The principal investigator is a physician postdoctoral fellow with a strong commitment to basic science research and a career in academic medicine. Her short term goal is to complete the studies outlined in this proposal and her long term goal is to become a well trained independent basic scientist in the field of molecular neuroendocrinology. This Mentored Clinical Scientist Development Award (K08) will enable her to gain the necessary skills required to progress in her development as an independent investigator. The institution and her mentors provide a supportive setting for her to flourish as a physician- scientist.
