ROLE OF NOVEL SOLUBLE TGF-BETA RECEPTOR IN THE KIDNEY

描述(改编自申请人摘要)：背景。转型 生长因子-β1(TGFb-1)是一种多功能细胞因子，调节细胞外信号转导。 各种各样的细胞过程，包括增殖、分化、 细胞外基质(ECM)的产生。它被认为是关键 中介物在多种疾病过程中的发病机制，包括 组织纤维化、炎症、血管损伤和肿瘤发生。在 在肾脏中，转化生长因子-β1的关键作用已经在几个肾脏中得到了很好的认识 以细胞外基质逐渐积累为特征的疾病导致 发生肾小球硬化，这是对损伤的最终常见反应。它的 转化生长因子-β异构体介导的多种生物学作用 I型和II型信号受体。然而，细胞和分子 转化生长因子-β受体参与信号传递的机制仍然很差 明白了。本提案的基础是在我们的 一种新型可溶性转化生长因子-βI型受体的实验室。我们有很强的 初步证据表明编码可溶性蛋白的mRNA转录本 受体在包括肾脏在内的各种组织中表达，而且它是 能够调节转化生长因子-β1信号。这项提案将重点放在进一步 新鉴定的可溶性转化生长因子-β受体及其功能的研究 肾小球内皮细胞和系膜细胞转化生长因子-β1信号转导功能的研究 细胞在体外和体内。 我们的假设是，一种自然产生的可溶性转化生长因子-β1 I型 受体调节转化生长因子-β1信号，发挥激动剂或 转化生长因子-β1的抑制作用依赖于其表达水平。 此外，sTbetaR-I在介导转化生长因子-β1的反应中起重要作用 肾小球损伤。我们将研究其在转化生长因子-β1中的功能作用 利用细胞培养系统和转基因小鼠进行信号传递。我们将研究 与已知的膜锚定的转化生长因子-β信号受体和 参与转化生长因子-β1信号转导的细胞内信号通路(S)及其 肾小球硬化体内模型中的功能作用。 关联性。这一建议将加深我们对该建筑群的了解 转化生长因子-β受体生物学和潜在的新的治疗方法 阻断特定的信号通路(S)对有害物质负责 转化生长因子-β1的作用，从而阻止或改变肾脏的进展 疾病。

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.