INSULIN STIMULATION OF GLUCOSE TRANSPORTER TRANSLOCATION

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The applicant proposes a multifaceted training program that will prepare him for a basic research career in the biology of endocrine and metabolic systems. This program will include formal didactic experience in graduate level courses at Harvard University, Harvard Medical School, and the Massachusetts Institute of Technology in the fields of molecular and cellular biology, virology, immunology, and genetics. The applicant will take advantage of numerous lectures and seminars sponsored by the above institutions, as well as by Massachusetts General Hospital and the Whitehead Institute for Biomedical Research. The core experience of Phase I will be to conduct a research project in the laboratory of Dr. Harvey F. Lodish, Member of the Whitehead Institute and Professor of Biology at MIT. During the applicant's past laboratory training with Mason Freeman, M.D., he developed an interest in vesicular transport and membrane targeting. Dr. Lodish shares this interest and has considerable experience in the field. The applicant's broad goal in his research plan is to dissect the signal transduction pathway. between the insulin receptor and glucose transporters. Small GTP-binding proteins of the rab family have been implicated in the regulation of vesicular transport. The specific aims of Phase I will be to test the hypothesis that a specific small GTP-binding protein, Rab3D, which recently has been cloned in Dr. Lodish's laboratory, participates in this signal transduction pathway. Other specific aims will be to investigate the biochemistry of Rab3D and to identify and clone other proteins that regulate glucose transport in insulin-responsive cells. Successful completion of the research plan promises to yield important insights into the syndromes of insulin resistance that characterize diabetes mellitus. The applicant's progress through Phase I will be monitored by an advisory committee of scientists and physicians appointed by Dr. Lodish and Dr. John T. Potts, Jr., the Chief of Medical Services at Massachusetts General Hospital. For Phase II the applicant will return to MGH and continue this line of research in collaboration with his Phase II sponsor, Dr. Joseph Avruch, who has a longstanding interest in insulin receptor signal transduction. Broadly stated, the applicant will investigate the regulatory proteins cloned during Phase I in animal models of insulin resistance and in human diabetes mellitus. More specific proposals for Phase II will be developed out of the experiments performed during Phase I.