Molecular mechanisms of renal injury

描述（由申请方提供）：肾小管间质纤维化是一种预后不良的指标，是终末期肾病发展的常见最终途径，无论其根本原因如何，最终导致肾组织破坏和不可逆的肾功能丧失。随着新诊断的慢性肾脏病和ESRD患者的发病率不断上升，对潜在机制的复杂理解和控制肾纤维化的新分子靶点的识别对于开发新疗法以扭转这一令人不安的趋势至关重要。肾小管周围毛细血管损失是进行性肾病的标志，并导致血流量减少，限制氧气输送到肾脏，导致慢性肾小管间质缺氧。细胞适应缺氧的关键介质是缺氧诱导因子（HIF）-1和-2，即碱性螺旋环螺旋转录因子，大多数已知其调节血管重塑、红细胞生成和能量代谢的能力。在这里，我们假设缺氧是肾脏疾病发展和进展的早期和起始事件，并且HIF信号的激活促进上皮细胞向间质细胞转化（EMT）和肾纤维化。由于肾HIF-1和HIF-2的生物学功能似乎是细胞类型依赖性的，我们提出的研究，a）调查的作用，个别HIF转录因子在进行性肾病的发病机制中的细胞类型特异性的背景下，在体内和B）旨在确定相关的HIF调节基因和信号通路。具体而言，我们建议开展以下研究：a）与Cre-loxP介导的重组结合以实现HIF-1 a和HIF-2 a的细胞类型特异性失活的进行性肾病的动物模型，B）检查特异性HIF靶基因及其在体外和体内EMT和纤维发生中的作用的研究，c）基因调控研究，和d）利用最新技术水平的基因表达和启动子阵列来鉴定相关HIF靶基因的研究。总的来说，这笔赠款旨在建立一个研究计划，研究HIF激活对肾脏疾病发展和进展至关重要的基因和信号网络表达的影响。拟议的研究将具有直接的临床意义，因为它们强烈鼓励旨在改善肾氧输送和消耗之间的平衡以阻止肾纤维化进展的治疗。公共卫生相关性这项拨款调查低氧环境在慢性肾脏疾病进展中的作用。一个主要的焦点是通过缺氧诱导因子（HIF）途径的信号转导。缺氧激活的分子通路的鉴定和表征有可能为新的治疗方法提供基础，以阻止肾瘢痕的进展。

DESCRIPTION (provided by applicant): Tubulointerstitial fibrosis is a poor prognostic indicator and common final pathway in the development of end-stage renal disease irrespective of the underlying cause, ultimately leading to the destruction of renal tissue and irreversible loss of renal function. As the incidence of patients with newly diagnosed chronic kidney disease and ESRD is rising, sophisticated understanding of underlying mechanisms and identification of new molecular targets to control renal fibrogenesis is fundamental in the development of new therapies to reverse this disturbing trend. Peri-tubular capillary loss is a hallmark of progressive renal disease and results in reduced blood flow that limits oxygen delivery to the kidney leading to chronic tubulointerstitial hypoxia. Key mediators of cellular adaptation to hypoxia are Hypoxia-Inducible-Factor (HIF)-1 and -2, basic-helix-loop- helix transcription factors, mostly known for their ability to regulate vascular remodeling, erythropoiesis, and energy metabolism. Here we hypothesize that hypoxia represents an early and initiating event in the development and progression of kidney disease, and that activation of HIF signaling promotes epithelial to mesenchymal transition (EMT) and renal fibrogenesis. Because the biological functions of renal HIF-1 and HIF-2 appear to be cell-type dependent, we propose studies, which a) investigate the role of individual HIF transcription factors in the pathogenesis of progressive renal disease in a cell-type specific context in vivo and b) are aimed at the identification of relevant HIF regulated genes and signaling pathways. Specifically we propose studies, which include: a) animal models of progressive renal disease in conjunction with Cre-loxP mediated recombination to achieve cell-type specific inactivation of HIF-1a and HIF-2a, b) studies that examine specific HIF target genes and their role in EMT and fibrogenesis in vitro and in vivo, c) gene regulatory studies, and d) studies utilizing state of the art gene expression and promoter arrays to identify relevant HIF target genes. Overall, this grant aims at establishing a research program, which investigates the effects of HIF activation on the expression of genes and signaling networks that are critical in the development and progression of renal disease. The proposed studies will have immediate clinical implications as they strongly encourage therapies that aim at improving the balance between renal oxygen delivery and consumption to halt the progression of renal fibrosis. PUBLIC HEALTH RELEVANCE This grant investigates the role of a low oxygen environment in the progression of chronic kidney disease. A main focus is on signaling through the Hypoxia-Inducible Factor (HIF) pathway. Identification and characterization of molecular pathways that are activated by hypoxia has the potential to provide the basis for new therapeutic approaches to halt the progression of renal scarring.