Mechanisms and Treatment of Kidney Fibrosis

项目摘要 慢性肾脏病（CKD）影响约15%的美国人口。虽然大范围的侮辱 在引发肾损伤时，纤维化是所有形式进行性CKD的标志。尽管在描绘 由于肾脏纤维化是通过多种途径导致的，因此对于这种严重的疾病没有特定的治疗方法。 TGF-β信号传导是多种组织中纤维化的中心介质，使其成为有吸引力的治疗靶标。 然而，由于这些细胞因子在人类生理学和病理学中具有广泛的作用， 挑战在于找到一种治疗策略，该治疗策略对于患病的靶组织是选择性的， 疗效和安全性特征。一种有希望的方法是破坏损伤组织中的TGF-β活化。TGF-β是 作为潜伏的、无活性的复合物分泌，其以高浓度螯合在细胞外基质中。一 调节TGF-β信号传导的关键步骤是通过结合α v（αv）激活潜在复合物， 整联蛋白与赖氨酸-甘氨酸-天冬氨酸（RGD）基序。在本提案的目标1中，我们将确定一部小说是否 TGF-β活化小分子RGD肽模拟物抑制剂可减少小鼠模型中的肾纤维化 肾毒性、局部缺血和尿路梗阻。我们的初步研究表明这种化合物 是安全和有效的，因此是一个非常有前途的候选人，为未来的翻译研究的患者。 开发有效的肾脏疾病治疗方法需要增加有关分子生物学的知识， 导致器官纤维化的机制。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，控制这些细胞响应于损伤而形成的细胞和分子途径是 没有被很好地理解。在目标2中，我们将研究α v（αv）整合素 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， 有可能确定一种新的治疗策略来治疗退伍军人的慢性肾病。

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.