Diabetes mellitus is a disease that afflicts over two million Americans. One gene therapy approach to treating this disease requires: 1) a safe vector to introduce candidate genes into islet cells to prevent their rejection, and 2) a method for producing an abundant supply of islet cells. This project addresses both of these requirements. By engineering a lentiviral system that consists of a cell line providing human immunodeficiency virus type 1 (HIV-1) packaging functions, a human immunodeficiency virus type 2 (HIV-2) transfer vector, and an envelope vector expressing the glycoprotein B (gB) envelope protein of cytomegalovirus (CMV), we hypothesize that one will produce virions that bind with high affinity to beta-islet cells and provide long-lasting expression of a transgene without an inflammatory response. The introduction of an excisable oncogene into pancreatic islet cells may allow their propagation with the ability to remove the transforming fragment of DNA. The work described will be performed in the outstanding environment of Harvard Medical School in the laboratory of Vikas P. Sukhatme, M.D., Ph.D., a molecular biologist committed to gene therapy applications. Collaborators include Terry B. Strom, M.D., expert in the use of immunoconstructs leading to cellular immunity and Towia A. Libermann, Ph.D., who has considerable experience in the manipulation of islet cells for allotransplantation. Consultant Norman Letvin, M.D., will provide expertise in the lentiviral genome and construction of chimeras. New methodologies the applicant will learn are cell line development, production of recombinant adenovirus, and isolation and transplantation of pancreatic islets. The applicant is a graduate of a combined M.D./Ph.D. program of the University of Texas Southwestern Medical Center at Dallas with 3.5 years of experience in protein folding in mammalian cells. The applicant has spent two years of his Nephrology fellowship developing a lentiviral vector system and investigating the mechanism of release of cytokines in response to adenoviral infection. He is absolutely committed to a career centered on basic research in an academic division of Nephrology. The combined quality of the sponsor, collaborators, and consultant in the environment of Harvard Medical School along with the applicant's previous research experience and ongoing commitment to research provides a unique opportunity for the applicant to achieve the goals of the project and become a successful independent investigator.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Clinical Investigator Award (CIA) (K08)
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Study Section
Special Emphasis Panel (SRC)
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Hyde, James F
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University of Florida
Internal Medicine/Medicine
Schools of Medicine
United States
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Lee, Pui Y; Li, Yi; Richards, Hanno B et al. (2007) Type I interferon as a novel risk factor for endothelial progenitor cell depletion and endothelial dysfunction in systemic lupus erythematosus. Arthritis Rheum 56:3759-69
Shah, Ronak; Beem, Elaine; Sautina, Laura et al. (2007) Mitomycin- and calcineurin-associated HUS, endothelial dysfunction and endothelial repair: a new paradigm for the puzzle? Nephrol Dial Transplant 22:617-20
Segal, Mark S; Shah, Ronak; Afzal, Aqeela et al. (2006) Nitric oxide cytoskeletal-induced alterations reverse the endothelial progenitor cell migratory defect associated with diabetes. Diabetes 55:102-9
Koc, Mehmet; Richards, Hanno B; Bihorac, Azra et al. (2005) Circulating endothelial cells are associated with future vascular events in hemodialysis patients. Kidney Int 67:1078-83
Beem, Elaine; Holliday, L Shannon; Segal, Mark S (2004) The 1.4-MDa apoptosome is a critical intermediate in apoptosome maturation. Am J Physiol Cell Physiol 287:C664-72
Koc, Mehmet; Bihorac, Azra; Segal, Mark S (2003) Circulating endothelial cells as potential markers of the state of the endothelium in hemodialysis patients. Am J Kidney Dis 42:704-12
Segal, Mark S; Bihorac, Azra; Koc, Mehmet (2002) Circulating endothelial cells: tea leaves for renal disease. Am J Physiol Renal Physiol 283:F11-9
Segal, M S; Beem, E (2001) Effect of pH, ionic charge, and osmolality on cytochrome c-mediated caspase-3 activity. Am J Physiol Cell Physiol 281:C1196-204