p90 Ribosomal S6 Kinase and Chronic Kidney Disease

描述（由申请人提供）：慢性肾脏疾病（CKD）通常被认为是一种不可逆的过程，通常导致终末期肾衰竭（ESRF），这是一种毁灭性疾病，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性的治疗方法之前，这种高发病率和相关的经济负担不太可能降低。间质纤维化是CKD的标志之一，通常被认为是CKD的决定性预后因素。在先前的体外研究中，我们发现p90核糖体S6激酶（p90 RSK）促进LDL受体相关蛋白-1（LRP-1）介导的间质成纤维细胞增殖和存活，导致肾间质纤维化和CKD的进展。然而，p90 RSK和LRP-1在体内肾纤维化发生中的作用从未被研究过。我们的中心假设是，在对慢性肾损伤的反应中，LRP-1和p90 RSK信号级联被激活，这促进了肾纤维化和CKD进展;并且p90 RSK的药理学抑制加重了肾损伤和纤维化。将使用体外和体内方法，通过解决以下特定目标来检验该假设 方法：特异性目的1将确定p90 RSK在新型诱导型成纤维细胞特异性p90 RSK转基因小鼠中的CKD中的作用。特异性目标2将确定LRP-1在独特的成纤维细胞特异性LRP-1敲除小鼠中的CKD中的作用。具体目标3将确定p90 RSK抑制对CKD治疗的疗效。这些研究将阐明p90 RSK和LRP-1在肾纤维化中的新功能，并为肾纤维化的潜在机制提供创新的见解。这些研究具有转化意义，它们将测试p90 RSK信号传导抑制在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开发。

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.