Cardiac allograft vasculopathy (CAV) is one of several terms that describe proliferative, neointimal lesions of coronary arteries following heart transplantation. As a leading cause of late death and graft failure, CAV remains a serious limitation to long-term success of heart transplantation. Alloantigen-dependent immune mechanisms play the primary role in initiating these lesions. However, translation of immune response into vascular pathology is postulated to require peptide growth factors that act on cells of the vascular wall. Among growth factors studies, expression of acidic fibroblast growth factor (aFGF, FGF-1) and its receptor (FGFR-1) in cardiac parenchyma is significantly associated with risk for development and severity of CAV. Alloantigen-independent factors appear to dynamically regulate the quantity of aFGF expressed in the myocardium, while alloantigen-dependent immune responses control the number and function of FGF receptors that transmit stimulatory signals to cells of the vascular wall. In addition to their actions on vascular cells, the investigators provide evidence that the FGF/FGFR ligand/receptor system directly affects alloantigen-dependent immune responses via a subset of T cells that express FGFR1. For these cells, FGF provides a costimulatory signal for IL-2 production and proliferation. Therefore, they propose that the allograft environment includes multiple inflammatory niches, each characterized by its own spectrum of antigen presenting cells, cytokines, and growth factors that provide costimulatory signals for alloantigen-activated T cells. Investigation of the mechanisms by which FGF costimulates T cells reveals that the TCR zeta-associated Syk kinase ZAP-70 associates with the cytoplasmic domain of the FGF receptor tyrosine kinase. Therefore, they hypothesize that ZAP-70 plays a critical role in integrating signals from the antigen receptor with those from the allograft environment via receptors such as FGFR1. In this competitive renewal application, they propose to define the molecular requirements for this association and identify the interactions of TCR and FGFR signaling pathways that result in costimulation.
Aim 1 will identify the sites in ZAP-70 required for its association with FGFR1.
Aim 2 will identify the sites in FGFR1 required for its association with ZAP-70.
Aim 3 will identify the molecules that link the TCR and FGFR signaling pathways. These studies will enhance our understanding of the factors within allograft environments that, together with antigen recognition, lead to T cell activation and survival and the translation of these events to CAV.
Showing the most recent 10 out of 14 publications
