ROLE OF NOVEL SOLUBLE TGF-BETA RECEPTOR IN THE KIDNEY

描述（改编自申请人的摘要）：背景。转化 生长因子-β 1（TGFB-1）是一种多功能细胞因子， 多种细胞过程，包括增殖，分化， 和细胞外基质（ECM）的产生。它被认为是 在多种疾病过程的发病机制中的介质，包括 组织纤维化、炎症、血管损伤和肿瘤发生。 在 在肾脏中，TGF-β 1的关键作用已经在几种肾脏疾病中得到了很好的认识。 特征为ECM进行性积累的疾病， 肾小球硬化症的发展，这是对损伤的最终常见反应。 其 多种生物学作用由TGF-β的异聚体复合物介导 I型和II型信号受体。 然而，细胞和分子 TGF-β受体参与信号传导的机制仍然很差， 明白 本建议的基础是我们在《圣经》中的发现。 TGF-β I型受体的一种新的可溶性形式的实验室。 我们有强大 初步证据表明，编码可溶性 受体在包括肾脏在内的各种组织中表达， 能够调节TGF-β 1信号传导。 该提案将进一步侧重于 新鉴定的可溶性TGF-β受体及其 TGF-β 1信号在肾小球内皮和系膜中的功能作用 细胞在体外和体内。 我们的假设是一种天然存在的可溶性I型TGF-β 1 受体调节TGF-β 1信号传导以作为激动剂或抑制剂发挥作用。 TGF-β 1抑制剂的作用取决于其表达水平。 此外，sTbetaR-I在介导TGF-β 1反应中是重要的。 肾小球损伤 我们将研究其在TGF-β 1 使用细胞培养系统和转基因小鼠进行信号传导。 我们将研究 与已知的膜锚定的TGF-β信号受体的相互作用， 参与TGF-β 1信号传导的细胞内信号传导途径，及其 在肾小球硬化症的体内模型中的功能作用。 本案无关 这一建议将进一步加深我们对该综合体的了解 TGF-β受体生物学和潜在导致新的治疗方法 以阻断负责有害细胞的特定信号通路， TGF-β 1的作用，从而预防或改变肾 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.