Accelerated transplant arteriosclerosis (TA), a manifestation of chronic rejection, is the leading cause of graft failure. The development of anti-HLA antibodies to donor HLA antigens is a major risk factor associated with TA. The overall goal of this proposal is to elucidate the signal transduction pathways that mediate HLA class I induced cell proliferation and the development of TA.
Under specific aim #1, we will establish whether anti-HLA antibodies induce tyrosine phoshphorylation of focal adhesion proteins and assembly of signaling complexes via an actin cytoskeleton dependent pathway in endothelium and smooth muscle. For this, we will establish whether exposure of cultured endothelial cells (EC) and smooth muscle cells (SMC) to monoclonal anti-HLA antibodies and anti-HLA antibodies from transplant patients with chronic rejection is accompanied by FAK phosphorylation and the generation of FAK/Src/Paxillin signaling complexes. We will determine if the phosphorylation of focal adhesion proteins is accompanied by alterations in the organization of the actin cytoskeleton and in the assembly of focal adhesions. We will explore the role of ROK, MLC phosphatase and ERK as upstream components of the class I signaling pathway. We will also determine if class I signaling stimulates anti-apoptotic signals by inducing tyrosine phosphorylation of PI3-kinase, Akt and Bad.
Under specific aim #2, we will identify the signaling pathways leading to MHC class I induced FGF receptor translocation in EC and SMC. For this, we will determine the role of the actin cytoskeleton, phosphorylation of FAK, Src, paxillin and assembly of focal adhesions in class I mediated FGFR translocation to distinct subcellular locations using flow cytometry and confocal microscopy. We will also assess the importance of ROK, ERK, MLC phosphatase in class I mediated FGF receptor translocation. The contribution of the FGF receptor tyrosine kinase activity and ERK phosphorylation to class I induced cell proliferation will be established.
Under aim #3, we will assess the expression of class I induced tyrosine phosphorylation, FGF receptors and anti-apoptotic proteins in clinical biopsy specimens from cardiac allografts with and without evidence of transplant arteriosclerosis. We will determine the correlation between protein phosphorylation events and protein expression with the incidence and time of onset of transplant arteriosclerosis and development of anti-HLA antibodies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI042819-08
Application #
7000319
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Macchiarini, Francesca
Project Start
1999-01-01
Project End
2007-12-31
Budget Start
2006-01-01
Budget End
2006-12-31
Support Year
8
Fiscal Year
2006
Total Cost
$372,291
Indirect Cost
Name
University of California Los Angeles
Department
Pathology
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Jin, Yi-Ping; Valenzuela, Nicole M; Zhang, Xiaohai et al. (2018) HLA Class II-Triggered Signaling Cascades Cause Endothelial Cell Proliferation and Migration: Relevance to Antibody-Mediated Transplant Rejection. J Immunol 200:2372-2390
Zhang, Qiuheng; Hickey, Michelle; Drogalis-Kim, Diana et al. (2018) Understanding the Correlation Between DSA, Complement Activation, and Antibody-Mediated Rejection in Heart Transplant Recipients. Transplantation 102:e431-e438
Salehi, Sahar; Sosa, Rebecca A; Jin, Yi-Ping et al. (2018) Outside-in HLA class I signaling regulates ICAM-1 clustering and endothelial cell-monocyte interactions via mTOR in transplant antibody-mediated rejection. Am J Transplant 18:1096-1109
Pearl, Meghan H; Zhang, Qiuheng; Palma Diaz, Miguel Fernando et al. (2018) Angiotensin II Type 1 receptor antibodies are associated with inflammatory cytokines and poor clinical outcomes in pediatric kidney transplantation. Kidney Int 93:260-269
Valenzuela, Nicole M; Reed, Elaine F (2017) Antibody-mediated rejection across solid organ transplants: manifestations, mechanisms, and therapies. J Clin Invest 127:2492-2504
Valenzuela, Nicole M; Thomas, Kimberly A; Mulder, Arend et al. (2017) Complement-Mediated Enhancement of Monocyte Adhesion to Endothelial Cells by HLA Antibodies, and Blockade by a Specific Inhibitor of the Classical Complement Cascade, TNT003. Transplantation 101:1559-1572
Weng, Patricia L; Alejos, Juan Carlos; Halnon, Nancy et al. (2017) Long-term outcomes of simultaneous heart and kidney transplantation in pediatric recipients. Pediatr Transplant 21:
Pearl, Meghan H; Nayak, Anjali B; Ettenger, Robert B et al. (2016) Bortezomib may stabilize pediatric renal transplant recipients with antibody-mediated rejection. Pediatr Nephrol 31:1341-8
Wallace, William Dean; Li, Ning; Andersen, Claus B et al. (2016) Banff study of pathologic changes in lung allograft biopsy specimens with donor-specific antibodies. J Heart Lung Transplant 35:40-8
Pizzo, Helen P; Ettenger, Robert B; Gjertson, David W et al. (2016) Sirolimus and tacrolimus coefficient of variation is associated with rejection, donor-specific antibodies, and nonadherence. Pediatr Nephrol 31:2345-2352

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