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（根据申请人的摘要改编）：背景。转型 生长因子-BETA1（TGFB-1）是一种多功能细胞因子，可调节A 各种各样的细胞过程，包括增殖，分化， 和细胞外基质（ECM）产生。它被认为是关键 介体在各种疾病过程的发病机理中 组织纤维化，炎症，血管损伤和肿瘤发生。 在 肾脏，TGF-B1的关键作用在几个肾脏中得到了很好的认可 以ECM的进行性积累为特征的疾病导致 肾小球硬化的发展，这是对损伤的最终共同反应。 它是 多种生物学作用是由TGF-beta的杂体复合物介导的 信号受体，I型和II。 但是，细胞和分子 TGF-β受体涉及信号传导的机制保持较差 理解。 本提案的基础是我们的发现 TGF-βI型受体的新型可溶性形式的实验室。 我们有强大 初步证据，表明编码可溶性的mRNA转录本 受体在包括肾脏在内的各种组织中表达，它是 能够调节TGF-BETA1信号传导。 该提议将重点放在进一步 新鉴定的可溶性TGF-β受体及其表征 肾小球内皮和肾小球中TGF-BETA1信号传导的功能作用 细胞体外和体内。 我们的假设是TGF-BETA1 I型的自然可溶性形式 受体调节TGF-BETA1信号传导，以作为激动剂或 TGF-BETA1作用的抑制剂取决于其表达水平。 此外，STBETAR-I对于介导TGF-BETA1作用很重要 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的信号传导。 我们将检查 与已知膜锚定的TGF-β信号受体的相互作用和 涉及TGF-BETA1信号传导的细胞内信号通路及其 在肾小球硬化体内模型中的功能作用。 关联。 这项建议将进一步我们对复杂的理解 TGF-β受体生物学，并有可能导致新型治疗方法 阻止负责有害的特定信号通路 TGF-BETA1的影响，从而预防或改变肾脏的进展 疾病。