Transient receptor potential (TRP) channels are a superfamily of polymodal receptor cation channels that mediate environmental and sensory signal transduction. TRP cation channel, subfamily V (TRPV) members are sensitive to various environmental stimuli such as: temperature changes, osmosensitivity and stress, and their ubiquitous expression suggests a role in both sensory and nonsensory transduction. Recently, we made the highly provocative observation that TRPV2 was profoundly underexpressed (greater than 20-fold) in Systemic Sclerosis (SSc) dermal fibroblasts compared to those from normal individuals, suggesting that TRPV channels may play a role in the pathogenesis of SSc. Other published studies have shown that TRPV1 and TRPV4 participate in the development of fibrotic lesions in animal models of fibrosis. Based on these studies we propose the hypothesis that: TGF- and TRPV channels establish an autocrine loop in fibroblasts and endothelial cells (EC) where TGF- expression decreases the expression of TRPV1 and TRPV2 and induces the expression of TRPV4. The reduction of TRPV1 and TRPV2 and the increase in TRPV4 in turn induce and maintain elevated TGF- levels creating a repetitive cycle which triggers myofibroblast differentiation in quiescent fibroblasts and induces endothelial to mesenchymal transition (EndoMT) in EC resulting in progressive tissue fibrosis and fibroproliferative vasculopathy. To test this hypothesis we will pursue the following Specific Aims:
SPECIFIC AIM 1 : Examine the effects of TRPV1, TRPV2 and TRPV4 agonists and antagonists in the presence and absence of TGF-, on the expression of profibrotic genes and of genes associated with myofibroblast activation in human dermal fibroblasts and with EndoMT in human dermal and pulmonary microvascular EC.
SPECIFIC AIM 2 : Evaluate the in vivo effects of Trpv1, Trpv2 and Trpv4 knockout employing the TGF- overexpression murine model of tissue fibrosis. Since there is currently no effective disease-modifying therapy to improve the devastating health consequences and high mortality associated with SSc, an urgent unmet need exists to identify potential targets to develop such therapies. The strengths of this proposal are: 1. It is supported by strong Preliminary Data demonstrating that alterations of the activity of TRPV1 and TRPV2 participate in the phenotypic differentiation of fibroblasts into activated myofibroblasts and in te induction of EndoMT in murine EC;and 2. They will provide valuable information regarding the initial molecular events that couple sensory signal transduction, inflammation and fibrosis in SSc. Thus, we believe these studies may provide important clues regarding SSc pathogenesis, and may identify potential novel therapeutic targets for this currently incurable disease.
Systemic Sclerosis (SSc) or Scleroderma is an autoimmune disorder of unknown etiology characterized by progressive fibrosis of skin and multiple internal organs with prominent and often severe alterations in the microvasculature. Transient Receptor Potential Vanilloid (TRPV) receptors are ion channels mediating the transduction of environmental and sensory signals that have recently been implicated in inflammation and in the development of fibrosis in animal models and have been shown by us to cause increased expression of TGF- and the generation of profibrotic activated myofibroblasts. The studies proposed here will investigate the role of TRPV channels in the pathogenesis of fibrosis and vasculopathy in SSc and will provide results that may allow the identification of novel and promising molecular targets for the development of new therapeutic approaches for this currently incurable disease.