Granulysin is a newly discovered cytolytic molecule co-expressed with granzymes and perforin in granules of CTL and NK cells. This molecule is expressed constitutively in NK cells but is expressed 3-5 days after activation of T cells. It is released from cytolytic granule upon stimulation via the TCR. Recombinant granulysin lyses tumor targets and bacteria, but does not lyse RBC. The purpose of this proposal is to better define the mechanism of action of granulysin, its target specificity, and expression in disease.
The specific aims are as follows: (1) Characterize the mechanism of action of granulysin, including the lytic activity of truncated or mutated forms of granulysin, formation of pores in membranes, association with lipids, ability to induce apoptosis, localization in target cells, and synergy with other molecules. (2) Better define the clinical relevance of granulysin by: (a) evaluating the specificity of lysis on panels of virally infected, microbial, and tumor target cells; and (b) evaluating expression of granulysin in disease sites, focusing on infection and cancer. (3) Generate a granulysin knock-out (KO) mouse in order to confirm its functional importance in vivo and to better characterize its mechanism of action, target specificity, and role in disease. Together these studies should provide a greater understanding of granulysin function and may permit application of this information to the design of new therapies of immune-mediate diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI043348-01
Application #
2666875
Study Section
Experimental Immunology Study Section (EI)
Program Officer
Hecht, Toby T
Project Start
1998-07-01
Project End
2001-06-30
Budget Start
1998-07-01
Budget End
1999-06-30
Support Year
1
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Stanford University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
800771545
City
Stanford
State
CA
Country
United States
Zip Code
94305
da Silva, Ana Paula Galvao; Unks, Donovan; Lyu, Shu-chen et al. (2008) In vitro and in vivo antimicrobial activity of granulysin-derived peptides against Vibrio cholerae. J Antimicrob Chemother 61:1103-9
Li, Q; Morimoto, K; Kobayashi, M et al. (2008) Visiting a forest, but not a city, increases human natural killer activity and expression of anti-cancer proteins. Int J Immunopathol Pharmacol 21:117-27
Wu, Bo; Huang, Chunhong; Kato-Maeda, Midori et al. (2008) IL-24 modulates IFN-gamma expression in patients with tuberculosis. Immunol Lett 117:57-62
Di Liberto, Diana; Buccheri, Simona; Caccamo, Nadia et al. (2007) Decreased serum granulysin levels in childhood tuberculosis which reverse after therapy. Tuberculosis (Edinb) 87:322-8
Chen, Xi; Howe, Jorg; Andra, Jorg et al. (2007) Biophysical analysis of the interaction of granulysin-derived peptides with enterobacterial endotoxins. Biochim Biophys Acta 1768:2421-31
Li, Q; Morimoto, K; Nakadai, A et al. (2007) Forest bathing enhances human natural killer activity and expression of anti-cancer proteins. Int J Immunopathol Pharmacol 20:3-8
Huang, Lisa P; Lyu, Shu-Chen; Clayberger, Carol et al. (2007) Granulysin-mediated tumor rejection in transgenic mice. J Immunol 178:77-84
Li, Qing; Morimoto, Kanehisa; Nakadai, Ari et al. (2007) Healthy lifestyles are associated with higher levels of perforin, granulysin and granzymes A/B-expressing cells in peripheral blood lymphocytes. Prev Med 44:117-23
Li, Qing; Dong, Chen; Deng, Anmei et al. (2005) Hemolysis of erythrocytes by granulysin-derived peptides but not by granulysin. Antimicrob Agents Chemother 49:388-97
Krensky, Alan M; Clayberger, Carol (2005) Granulysin: a novel host defense molecule. Am J Transplant 5:1789-92