My commitment to basic research has remained unchanged since my first experience in a biochemistry research laboratory. Although I have spent much of the last 6 years obtaining training in clinical medicine and clinical endocrinology, I now intend to devote myself to basic research as I make the transition to full faculty status. Of course, I have not abandoned my physician roots; indeed, I believe that increasing my critical thinking in the laboratory ultimately will augment my clinical wisdom. Since my entry into the laboratory of Dr. Peter Arvan, I have expanded my fund of knowledge in the area of thyroid cell biology, which has given me great opportunity to develop in my career toward the goal of becoming established both as a basic scientist and thyroidologist. While advancing in academic medicine, I feel that I am steadily becoming a productive and increasingly independent investigator. I plan eventually to return to some (20%) clinical and teaching responsibilities, while maintaining my central thrust (80%) in the laboratory. I have been fortunate in my recent studies of processing and export of thyroglobulin (Tg) from the endoplasmic reticulum of cultured thyroid cells, since thyroid glands (and cell lines) are readily available for cell culture studies, and they provide an excellent model of the synthesis and export of this polypeptide prohormone. As described in the body of this grant, Tg is an ideal molecule in which to study the conformational maturation of nascent secretory proteins, because of its enormous size and relatively slow folding and post-translational processing. Further, my preliminary data have identified specific Tg folding intermediates that exhibit transient yet intimate interactions with several resident proteins in the endoplasmic reticulum. Excitingly, this area of molecular cell biology has witnessed a recent explosion of interest. Perhaps most important, the proposed studies should help to understand structural determinants that influence thyroid hormone formation. My association with my primary sponsor has been quite favorable. In addition to introducing me to underlying scientific principles, the Arvan laboratory has helped me develop my skills in creative thinking, organization and planning, and establishing rigorous scientific proof. In addition to our one-on-one meetings, our lab group meetings, journal clubs, seminars, and grand rounds all contribute to my general education. Thus, the lab provides an extremely stimulating working environment. In addition to Dr. Arvan, I interact regularly with two PhD-postdoctoral fellows in the lab with whom I have close contact. Further, there are several more senior scientists who are readily available for consultation and advice, the most important including Drs. Jeffrey Flier (Endocrine division chief), Enrique Silva (Head, Thyroid Unit), George Scheele (molecular and cell biologist, serving as secondary sponsor), and Karl Matlin (Dept. of Cell Biology, Harvard Medical School), all who are well informed of my progress and are only a few steps away. Overall, I believe this training will be of profound consequence in my ability to succeed as an independent scientist and in making the transition to junior faculty.