Mechanisms and Treatment of Kidney Fibrosis

项目摘要 慢性肾脏疾病(CKD)影响着大约15%的美国人口。尽管有一系列的侮辱 引发肾脏损伤，纤维化是所有形式进展性CKD的标志。尽管在划定方面取得了进展 关于导致肾脏纤维化的途径，目前还没有针对这一严重疾病的特效药。 转化生长因子-β信号通路是多种组织纤维化的中心介质，使其成为一个有吸引力的治疗靶点。 然而，由于这些细胞因子在人类生理和病理中具有广泛的作用， 一直面临的挑战是找到一种治疗策略，对患病的靶组织进行选择性的改善 疗效和安全性简介。一种有希望的方法是干扰损伤组织中转化生长因子-β的激活。转化生长因子-β是 以一种潜在的、不活跃的复合体的形式分泌，在细胞外基质中以高浓度的形式隔离。一个 转化生长因子-β信号调节的关键步骤是通过结合αv(αv)激活潜伏复合体。 赖氨酸-甘氨酸-天冬氨酸(RGD)基序的整合素。在本提案的目标1中，我们将确定一部小说是否 小分子RGD肽抑制转化生长因子-β活化可减轻小鼠肾脏纤维化 肾毒性、缺血和尿路梗阻。我们的初步研究表明，这种化合物 是安全有效的，因此是未来患者转化性研究的极有希望的候选者。 开发肾脏疾病的有效治疗方法需要增加对分子的了解 导致器官进行性纤维化的机制。肌成纤维细胞，来源于血管周围 间充质祖细胞是器官纤维化中细胞外基质沉积的主要来源。 然而，控制这些细胞的形成以应对伤害的细胞和分子途径是 不是很清楚。在目标2中，我们将研究αv(αv)整合素的分子机制 调节损伤后肌成纤维细胞的增殖和分化。 这些临床前研究将促进对器官纤维化机制的了解，并具有 确定一种治疗退伍军人慢性肾脏疾病的新治疗策略的可能性。

Project Summary Chronic kidney disease (CKD) affects ~15% of the U.S. population. Although a broad range of insults initiate kidney injury, fibrosis is a hallmark of all forms of progressive CKD. In spite of advances in delineating pathways that contribute to kidney fibrosis, there are no specific treatments for this serious disorder. TGF-β signaling is a central mediator of fibrosis in multiple tissues making it an attractive therapeutic target. However, because these cytokines have a wide range of roles in human physiology and pathology, the challenge has been to find a therapeutic strategy that is selective for the diseased target tissue to improve efficacy and safety profiles. A promising approach is to disrupt TGF-β activation in the injured tissue. TGF-β is secreted as a latent, inactive complex that is sequestered in high concentrations in the extracellular matrix. A critical step in the regulation of TGF-β signaling is activation of the latent complex by binding of alpha v (αv) integrins to lysine-glycine-aspartic acid (RGD) motifs. In Aim 1 of this proposal, we will determine if a novel small molecule RGD peptidomimetic inhibitor of TGF-β activation will reduce kidney fibrosis in mouse models of nephrotoxicity, ischemia and urinary tract obstruction. Our preliminary studies indicated that this compound is safe and effective and thus a highly promising candidate for future translational studies in patients. Developing effective treatments for kidney disease requires increased knowledge about molecular mechanisms that drive progressive fibrosis of the organ. Myofibroblasts, derived from peri-vascular mesenchymal progenitor cells are the principal source of extracellular matrix deposition in organ fibrosis. However, the cellular and molecular pathways that control the formation of these cells in response to injury are not well understood. In Aim 2, we will investigate the molecular mechanisms by which alpha v (αv) integrins regulate the proliferation and differentiation of myofibroblasts after injury. These pre-clinical studies will advance knowledge about mechanisms of organ fibrosis and have the potential to identify a novel therapeutic strategy to treat chronic kidney disease in veterans.