This proposal is designed to provide the principle investigator. Maria Jorgensen, with the scientific experience necessary to embark on a successful independent career as an academic medical scientist. During her training in the M.D./Ph.D. program at Tufts University, she gained skills in protein and immunochemistry as well as basic molecular biology in the laboratory of Drs. Bruce and Barbara Furie, while defining the signals which specify post-translational processing events during the synthesis of blood clotting proteins. After clinical training in internal medicine and hematology, Dr. Jorgensen has spent the last two years studying megakaryopoiesis in the laboratory of Kenneth Kaushansky at the University of Washington. She hopes to continue this course of study over the next four years while making a gradual transition to independent status. The proposed research plan consists of efforts to define, through screening of megakaryocyte expression libraries, genes involved in the process of megkaryopoiesis. Two different strategies should lead to genes which are either sufficient to induce commitment to the megakaryocyte lineage, or those which are necessary for carrying out the process of differentiation in that lineage. Through these experiments Dr. Jorgensen will gain expertise in preparing and screening cDNA libraries, including challenging techniques such as subtractive hybridization. Complete characterization and functional evaluation of the genes identified through the proposed strategies will provide a firm basis for future, independent grant proposals. Additionally, this work will foster a thorough appreciation of central issues in the fields of differentiation and development in general. Dr. Kaushansky, an authority on thrombopoietin and the regulation of megakaryopoiesis, will continue to serve as Dr. Jorgensen's sponsor and research mentor. In addition an advisory committee, including senior members with expertise in molecular and cellular hematopoiesis, will oversee her research progress and career development. Numerous other faculty members are engaged in research on differentiation and development, including hematopoiesis, and conferences and lectures by experts in these fields are plentiful. The University of Washington, with its extensive research community and world-class facilities, provides and ideal setting for Dr. Jorgensen's career development as an independent, productive scientist.
