Vascular restenosis induced by arterial trauma is one of the most critical factors which limits the success o solid organ transplantation and coronary interventional procedures. A popular hypothesis is that the cytokine-induced activation and proliferation of VSMC in the media, culminating in intimal hyperplasia, is the most critical cellular event in formation of both cardiac allograft vasculopathy (CAV) and balloon angioplastyinduced restenosis. Identification and functional characterization gene products involved in VSMC activation is a promising approach for the identification of targets to combat proliferative arteriopathy observed in vascular proliferative disorders. Our hypothesis is that allograft inflammatory factor-I (AIF-1) promotes development of vascular proliferative disease based on its ability to respond to inflammatory cytokines and participate in the growth stimulatory pathways leading to proliferation of VSMC. We have recently shown that modulation of AIF- 1 levels in human VSMC impacts the growth of these cells.
The first aim of this project will determine the mechanism of AIF-l growth promoting effects in human VSMC through a combination of flow cytometric analysis and investigation of expression and turnover of cell cycle-associated proteins. We will also identify regions that mediate these effects by site-specific modification of the AIF- 1 protein. We have determined that AIF- 1 partners with several cytoplasmic proteins, including a newly described growth factor-activated lipid kinase termed LCBK5.
The second aim of this proposal will determine the functional significance of the AIF- 1-LCBK5 interaction and characterize the other AIF-1-interacting peptides we have identified. Expression of AIF- 1 transcript is induced in mitogen-stimulated peripheral blood lymphocytes (PBL), and its expression in endomyocardial biopsies from transplanted hearts correlates with ISHLT rejection scores.
A final aim of this proposal will correlate AIF-1 transcript levels in endomyocardial biopsies and PBL from heart transplant recipients with development of arteriopathy as determined by several clinical and imaging indices. It is anticipated that completion of these studies will implicate expression of this novel protein as a target of anti-restenotic therapy and a surrogate marker of transplant restenosis.
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