): This application for a Mentored Clinical Scientist Development Award proposes to train a physician specializing in hematology/oncology to become an independent investigator in the molecular biology of tissue proliferation. Training will include didactic coursework, seminars, a research advisory committee, and research on the molecular mechanisms of G protein induced tissue proliferation. For the past four years, the applicant has been performing an internal medicine residency and a medical oncology fellowship. Prior to medical school the applicant has two years of laboratory experience in the biology of cell growth. G proteins amplify extracellular signals, creating intracellular responses that control a wide variety of physiologic events, including proliferation. The three best characterized G protein signaling pathways involve Gs, Gi, and Gq, whose alpha subunits alpha-s, alpha-i, and alpha-q) stimulate adenylyl cyclase, inhibit adenylyl cyclase, or stimulate phosphatidylinositol-specific phospholipase C, respectively. The G protein alpha-s subunit (alpha-s), when constitutively activated by point mutations (alpha-s*), causes transformation of tissue culture cells, tumors in transgenic mice, and tumors in certain human tissues (thyroid, adrenal, testes). Mutationally activated alpha-i (alpha-i*) and alpha-q (alpha-q*) transform tissue culture cells, but have not been expressed in transgenic animals or been shown to directly cause human disease. Previous pharmacological studies have been implicated either Gi or Gq signaling pathways in proliferation of hepatic, mammary, and hematopoietic tissues. This proposal aims to directly study the proliferation effects of the Gi and Gq signaling pathways in vivo by expressing mutationally activated alpha-i (alpha-i*) and alpha-q (alpha-q*) in transgenic mice. By using a tetracycline transactivator system (tTA system), alpha-i* and alpha-q* will be expressed in a tissue and temporal specific manner. This temporal control will allow gene expression in a fully developed animal, and avoid likely developmental effects of alpha-i* and alpha-q* expression. By studying the proliferative effects of alpha-i* and alpha-q* we will gain insights into the natural controls of tissue proliferation, and may identify G protein mutants in human tumors. Ultimately, knowledge about new oncogenes may allow novel strategies to control proliferation of cancerous cells.
| Redfern, C H; Degtyarev, M Y; Kwa, A T et al. (2000) Conditional expression of a Gi-coupled receptor causes ventricular conduction delay and a lethal cardiomyopathy. Proc Natl Acad Sci U S A 97:4826-31 |
| Redfern, C H; Coward, P; Degtyarev, M Y et al. (1999) Conditional expression and signaling of a specifically designed Gi-coupled receptor in transgenic mice. Nat Biotechnol 17:165-9 |
