p90 Ribosomal S6 Kinase and Chronic Kidney Disease

描述(申请人提供)：慢性肾脏疾病(CKD)通常被认为是一个不可逆转的过程，通常会导致终末期肾功能衰竭(ESRF)，这是一种毁灭性的疾病，其发病率在过去十年中增长了约20%-25%，约占美国总人口的10%。在我们更好地了解CKD的分子和细胞发病机制并开发出有效和特异的治疗方法之前，这种高发病率和相关的经济负担不太可能得到减少。间质纤维化是CKD的标志之一，通常被认为是CKD的决定预后因素。在以往的体外研究中，我们发现p90核糖体S6激酶(P90RSK)促进低密度脂蛋白受体相关蛋白-1(LRP-1)介导的间质成纤维细胞的增殖和存活，导致肾间质纤维化和CKD的进展。然而，p90RSK和LRP-1在体内肾纤维化形成中的作用从未被研究过。我们的中心假设是，在慢性肾损伤的反应中，LRP-1和p90RSK信号级联被激活，促进了肾脏纤维化和CKD的进展；药物抑制p90RSK可以减轻肾脏损伤和纤维化。这一假设将通过使用体外和体内两种方法解决以下具体目标来验证 方法：特异靶1将确定p90RSK在新型可诱导成纤维细胞特异性p90RSK转基因小鼠CKD中的作用。特定目的2将确定LRP-1在独特的成纤维细胞特异性LRP-1基因敲除小鼠CKD中的作用。特异性靶点3将决定p90RSK抑制治疗CKD的疗效。拟议的研究将阐明p90RSK和LRP-1在肾纤维化中的新功能，并为肾纤维化的发生机制提供创新的见解。这些研究具有翻译意义，它们将测试抑制p90RSK信号在CKD治疗中的治疗效果，并将刺激旨在阻止或逆转CKD进展的新型临床干预措施的发展。

DESCRIPTION (provided by applicant): Chronic kidney disease (CKD) is usually considered to be an irreversible process that often results in end stage renal failure (ESRF), a devastating disorder whose incidence has grown approximately 20-25% during the past decade and accounts about 10% of the total population in the United States. It is unlikely that this high morbidity and associated financial burden will be reduced until we have a better understanding of the molecular and cellular pathogenesis of CKD and develop effective and specific treatment. Interstitial fibrosis, one of the hallmarks of CKD, is generally considered to be the determinant prognosis factor of CKD. In previous in vitro studies, we discovered that p90 ribosomal S6 kinase (p90RSK) promotes LDL receptor- related protein-1 (LRP-1)-mediated interstitial fibroblast proliferation and survival, leading to renal interstitial fibrosis and the progression o CKD. However, the roles of p90RSK and LRP-1 in renal fibrogenesis in vivo have never been investigated. Our central hypothesis is that, in response to chronic kidney injury, the LRP-1 and p90RSK signaling cascade is activated, which promotes renal fibrosis and CKD progression; and that pharmacological inhibition of p90RSK alleviates kidney damage and fibrosis. This hypothesis will be tested by addressing the following specific aims using both in vitro and in vivo approaches: Specific Aim 1 will determine the role of p90RSK in CKD in the novel inducible fibroblast-specific p90RSK transgenic mice. Specific Aim 2 will determine the role of LRP-1 in CKD in the unique fibroblast-specific LRP-1 knockout mice. Specific Aim 3 will determine the therapeutic efficacy of p90RSK inhibition for CKD treatment. The proposed investigations will illuminate novel functions of p90RSK and LRP-1 in renal fibrosis and provide innovative insights into the mechanisms underlying renal fibrogenesis. These studies have translational significance that they will test the therapeutic efficacy of inhibition of p90RSK signaling in the treatment of CKD and will stimulate the development of novel clinical interventions designed to halt or reverse the progression of CKD.