ROLE OF NOVEL SOLUBLE TGF-BETA RECEPTOR IN THE KIDNEY

描述（改编自申请人摘要）：背景。转换

DESCRIPTION (Adapted from the Applicant's Abstract): Background. Transforming growth factor-beta1 (TGFB-1) is a multifunctional cytokine which regulates a wide variety of cellular processes, including proliferation, differentiation, and extracellular matrix (ECM) production. It has been implicated as the key mediator in the pathogenesis of a wide variety of disease processes including tissue fibrosis, inflammation, vascular injury, and tumorigenesis. In the kidney, the critical role of TGF-B1 has been well recognized in several renal diseases characterized by progressive accumulation of ECM leading to the development of glomerulosclerosis, a final common response to injury. Its multiple biological actions are mediated by heteromeric complex of TGF-beta signaling receptors, type I and II. However, the cellular and molecular mechanisms involved in signaling by the TGF-beta receptors remain poorly understood. The basis of the present proposal is the discovery in our laboratory of a novel soluble form of TGF-beta type I receptor. We have strong preliminary evidence indicating that mRNA transcript encoding the soluble receptor is expressed in various tissues including the kidney and that it is capable of modulating TGF-beta1 signaling. This proposal will focus on further characterization of the newly identified soluble TGF-beta receptor and its functional role in TGF-beta1 signaling in glomerular endothelial and mesangial cells in vitro and in vivo. Our hypothesis is that a naturally-occurring soluble form of TGF-beta1 type I receptor modulates TGF-beta1 signaling to function either as an agonist or an inhibitor of TGF-beta1 actions depending on the level of its expression. Further, the sTbetaR-I is important in mediating TGF-beta1 actions in response to glomerular injury. We will investigate its functional role in TGF-beta1 signaling using cell culture system and transgenic mice. We will examine interaction with the known membrane-anchored TGF-beta signaling receptors and the intracellular signaling pathway(s) involved in TGF-beta1 signaling, and its functional role in an in vivo model of glomerulosclerosis. Relevance. This proposal will further our understanding of the complex TGF-beta receptor biology and potentially lead to novel therapeutic approaches to block the specific signaling pathway(s) responsible for the deleterious effects of TGF-beta1, and thereby prevent or modify progression of renal disease.