The long-term objectives of this project are to define the role of the granzyme B pathway in accelerated graft atherosclerosis, and its predominant mechanisms of pathogenesis in this setting. Recent data has underscored the fact that the granzyme B pathway plays a central role in transplant rejection, acting through induction of death and dysfunction of target cells through cleavage of highly specific intracellular and extracellular substrates. In preliminary studies, we have demonstrated that differentiated vascular smooth muscle cells (vSMCs) are preferentially and highly susceptible to granzyme B-induced proteolysis, and have observed that fibrillin-1 (a component of microfibrils in extracellular matrix which is prominent in blood vessels) is efficiently cleaved by granzyme B. We hypothesize that the granzyme B pathway plays a critical role in initiating and driving the specific vascular phenotype in AGA, through induction of ongoing damage of differentiated vSMCs, and cleavage of a critical extracellular matrix signal which leads to dysregulation of smooth muscle cell and endothelial cell function. We will address this hypothesis through the following specific aims: (1) Define the activity, targets and mechanisms of the granzyme B-induced dysfunction in vivo in human cardiac transplantation using unique probes of granzyme B-induced cleavage of intracellular and extracellular substrates; (2) Define the functional consequences of the granzyme B pathway on vessel structure and function, including intact vessels and isolated smooth muscle cells in vitro; (3) Address the role of granzyme B in development of AGA lesions in vivo by examining the effects of deficiency of GrB either in the whole animal or in distinct microenvironments, using granzyme B-deficient mice or mice expressing intracellular or secreted forms of a potent GrB inhibitor in vascular smooth muscle cells.
| Huang, Jie; Huffman, Jennifer E; Yamakuchi, Munekazu et al. (2014) Genome-wide association study for circulating tissue plasminogen activator levels and functional follow-up implicates endothelial STXBP5 and STX2. Arterioscler Thromb Vasc Biol 34:1093-101 |
| Mammen, Andrew L; Mahoney, James A; St Germain, Amanda et al. (2011) A novel conserved isoform of the ubiquitin ligase UFD2a/UBE4B is expressed exclusively in mature striated muscle cells. PLoS One 6:e28861 |
| Wehner, Jennifer R; Fox-Talbot, Karen; Halushka, Marc K et al. (2010) B cells and plasma cells in coronaries of chronically rejected cardiac transplants. Transplantation 89:1141-8 |
| Harris, Tamia A; Yamakuchi, Munekazu; Kondo, Maiko et al. (2010) Ets-1 and Ets-2 regulate the expression of microRNA-126 in endothelial cells. Arterioscler Thromb Vasc Biol 30:1990-7 |
| Lowenstein, Charles J; Cameron, Scott J (2010) High-density lipoprotein metabolism and endothelial function. Curr Opin Endocrinol Diabetes Obes 17:166-70 |
| Ferlito, Marcella; Fulton, William B; Zauher, Mohamed A et al. (2010) VAMP-1, VAMP-2, and syntaxin-4 regulate ANP release from cardiac myocytes. J Mol Cell Cardiol 49:791-800 |
| Soong, Thing Rinda; Pathak, Arvind P; Asano, Hiroshi et al. (2010) Lymphatic injury and regeneration in cardiac allografts. Transplantation 89:500-8 |
| Jeong, Youngtae; Chaupin, Damian F; Matsushita, Kenji et al. (2009) Aldosterone activates endothelial exocytosis. Proc Natl Acad Sci U S A 106:3782-7 |
| Kirk, A D; Morrell, C N; Baldwin 3rd, W M (2009) Platelets influence vascularized organ transplants from start to finish. Am J Transplant 9:14-22 |
| Murata, Kazunori; Baldwin 3rd, William M (2009) Mechanisms of complement activation, C4d deposition, and their contribution to the pathogenesis of antibody-mediated rejection. Transplant Rev (Orlando) 23:139-50 |
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