This application for a Physician/Scientist Award is designed to provide broad, intensive training in molecular biology in preparation for a career as an independent investigator in the field of medical oncology. This application outlines a detailed program consisting of formal didactic education, an in-depth experience in basic research, and a long-range commitment to ongoing clinical investigation. Phase I of this proposal will include graduate level education at Harvard Medical School and Harvard University in molecular biology, genetics, cell biology, and molecular immunology. Phase I will simultaneously consist of intensive training in basic research in the lab of Dr. Philip Leder at the Harvard Medical School. The proposed research project will study the molecular biology of interleukin 4 (IL4) and its receptor. IL4 is a cytokine that has pleiotropic effects on a number of' hematopoietic cells in vitro and Dr. Leder's lab has shown that IL4 has a potent antitumor effect in vivo. The IL4 receptor is a member of a superfamily of cytokine receptors that includes those for IL2, IL3, IL6, IL7, GM-CSF, G-CSF, and erythropoietin. As a first step toward understanding the functional significance of conserved motifs in this receptor superfamily and eventually understanding in detail the interaction of IL4 with its receptor, this proposal outlines a structure-function analysis of IL4 and its receptor. IL4 is species specific in its function and therefore hybrid molecules between mouse IL4 and human IL4 as well as their receptors will be generated and functionally assayed. Once specific functionally important regions of the proteins are identified alanine-scanning mutagenesis will be used to asses the functional significance of specific amino acid side chains. This structure-function analysis will not only enhance understanding of cytokine-receptor interactions but may also lead to the development of novel antineoplastic agents. Progress during this phase of the applicant's training will be monitored by a committee of physicians and scientists chosen by Dr. Leder and Dr. John Potts. Phase II of this proposal will be under the guidance of Dr. Leder and Dr. Kurt Isselbacher. It is anticipated that during Phase II basic studies of IL4 will continue and the clinical use of IL4 as an immunotherapeutic agent in the treatment of cancer will be studied.
| Morrison, B W; Leder, P (1994) neu and ras initiate murine mammary tumors that share genetic markers generally absent in c-myc and int-2-initiated tumors. Oncogene 9:3417-26 |
