ROLE OF NOVEL SOLUBLE TGF-BETA RECEPTOR IN THE KIDNEY

新型可溶性 TGF-β 受体在肾脏中的作用

• 批准号: 6087959
• 负责人: MARY E CHOI
• 金额: $ 2.85万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-06-01 至 2000-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6087959
• 关键词: biological signal transduction; genetically modified animals; glomerulosclerosis; growth factor receptors; laboratory mouse; laboratory rat; molecular pathology; receptor expression; transforming growth factors

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.

描述（改编自申请人的摘要）：背景。转型 生长因子-β1 (TGFB-1) 是一种多功能细胞因子，可调节 多种细胞过程，包括增殖、分化、 和细胞外基质（ECM）的产生。它被牵连为关键 多种疾病过程发病机制中的介质，包括 组织纤维化、炎症、血管损伤和肿瘤发生。 在 在肾脏中，TGF-B1 的关键作用已在多种肾脏疾病中得到充分认识。 以 ECM 逐渐积累为特征的疾病，导致 肾小球硬化症的发展，这是对损伤的最终常见反应。 它是 TGF-β 异聚复合物介导多种生物作用 信号传导受体，I 型和 II 型。 然而，细胞和分子 TGF-β受体信号传导机制仍然很差 明白了。 本提案的基础是我们的发现 实验室开发了一种新型可溶形式的 TGF-β I 型受体。 我们有强大的 初步证据表明 mRNA 转录物编码可溶性 受体在包括肾脏在内的多种组织中表达， 能够调节 TGF-β1 信号传导。 该提案将进一步关注 新发现的可溶性 TGF-β 受体的表征及其 肾小球内皮和系膜中 TGF-β1 信号传导的功能作用 体外和体内的细胞。 我们的假设是天然存在的可溶形式的 I 型 TGF-β1 受体调节 TGF-β1 信号传导以充当激动剂或拮抗剂 TGF-β1 抑制剂的作用取决于其表达水平。 此外，sTbetaR-I 在介导 TGF-β1 反应中发挥重要作用 导致肾小球损伤。 我们将研究其在 TGF-beta1 中的功能作用 使用细胞培养系统和转基因小鼠进行信号传导。 我们将检查 与已知的膜锚定 TGF-β 信号受体的相互作用 参与 TGF-β1 信号传导的细胞内信号传导途径及其 在肾小球硬化体内模型中的功能作用。 关联。 该提案将加深我们对复杂问题的理解 TGF-β受体生物学并可能带来新的治疗方法 阻断负责有害物质的特定信号通路 TGF-β1 的作用，从而预防或改变肾病的进展 疾病。