A rigorous program of classroom and laboratory training in molecular biology and immunology is proposed as the basis for a career as an independent investigator in infectious disease. The program will consist of two phases to allow in-depth study of molecular biology and immunology at the graduate level and provide intensive training in the laboratory in order to foster my intellectual development as a physician-scientist. During Phase I graduate courses in genetics, molecular biology, virology, and immunology at Harvard University and the Massachusetts Institute of Technology will provide a didactic framework for the proposed experiments. At the same time, work will commence in the laboratory of Dr. Richard Young of the Whitehead Institute and MIT, who will serve as Phase I sponsor. Dr. Young has been chosen for his expertise in molecular biology and immunology as evidenced by his contributions to the understanding of cellular immunity directed against mycobacterial antigens. Moreover, as a member of the National Cooperative Vaccine Development Group for the Acquired Immune Deficiency Syndrome (NCVDG-AIDS), Dr. Young is committed to applying the resources at his disposition towards the understanding of the genetics and immunology of human immunodeficiency virus (HIV). I proposed to study the epitopes of HIV antigens that elicit a cytotoxic T-lymphocyte (CTL) response from the host. These epitopes will be determined by using vaccinia/HIV recombinants carrying segments of HIV genes and by using a series of overlapping synthetic peptides derived from the predicted amino acid sequences of HIV proteins. In addition, techniques for clonal expansion of HIV-specific cytotoxic T-lymphocytes will be developed. Progress during Phase I will be monitored by a committee of scientists and physicians selected by Dr. Young and Dr. John T. Potts, Chief of Medicine at Massachusetts General Hospital. Dr. Martin S. Hirsch, Professor of Medicine at HMS and leader of the AIDS research group within the MGH Infectious Disease Unit will serve as the Phase II clinical sponsor along with Dr. Robert T. Schooley, Associate Professor of Medicine (HMS) and member of the NCVDG-AIDS. Although specific goals of Phase II are not yet defined, it is expected that the results of the Phase I series will be extended to provide a greater understanding of the cellular immune response to HIV infection.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Physician Scientist Award (K11)
Project #
7K11AI000929-03
Application #
3085302
Study Section
Acquired Immunodeficiency Syndrome Research Review Committee (AIDS)
Project Start
1990-07-01
Project End
1994-03-31
Budget Start
1990-07-01
Budget End
1991-03-31
Support Year
3
Fiscal Year
1990
Total Cost
Indirect Cost
Name
University of Colorado Denver
Department
Type
Schools of Medicine
DUNS #
065391526
City
Aurora
State
CO
Country
United States
Zip Code
80045
Alfano, Randall W; Leppla, Stephen H; Liu, Shihui et al. (2008) Cytotoxicity of the matrix metalloproteinase-activated anthrax lethal toxin is dependent on gelatinase expression and B-RAF status in human melanoma cells. Mol Cancer Ther 7:1218-26
Gupta, Pradeep K; Liu, Shihui; Batavia, Mariska P et al. (2008) The diphthamide modification on elongation factor-2 renders mammalian cells resistant to ricin. Cell Microbiol 10:1687-94
Wickliffe, Katherine E; Leppla, Stephen H; Moayeri, Mahtab (2008) Anthrax lethal toxin-induced inflammasome formation and caspase-1 activation are late events dependent on ion fluxes and the proteasome. Cell Microbiol 10:332-43
Liu, Shihui; Wang, Hailun; Currie, Brooke M et al. (2008) Matrix metalloproteinase-activated anthrax lethal toxin demonstrates high potency in targeting tumor vasculature. J Biol Chem 283:529-40
Chen, Kuang-Hua; Liu, Shihui; Bankston, Laurie A et al. (2007) Selection of anthrax toxin protective antigen variants that discriminate between the cellular receptors TEM8 and CMG2 and achieve targeting of tumor cells. J Biol Chem 282:9834-45
Liu, Shihui; Leung, Howard J; Leppla, Stephen H (2007) Characterization of the interaction between anthrax toxin and its cellular receptors. Cell Microbiol 9:977-87
Liu, Shihui; Redeye, Vivien; Kuremsky, Jeffrey G et al. (2005) Intermolecular complementation achieves high-specificity tumor targeting by anthrax toxin. Nat Biotechnol 23:725-30
McFarland, E J; Harding, P A; Luckey, D et al. (1994) High frequency of Gag- and envelope-specific cytotoxic T lymphocyte precursors in children with vertically acquired human immunodeficiency virus type 1 infection. J Infect Dis 170:766-74
McFarland, E J; Curiel, T J; Schoen, D J et al. (1993) Cytotoxic T lymphocyte lines specific for human immunodeficiency virus type 1 Gag and reverse transcriptase derived from a vertically infected child. J Infect Dis 167:719-23