Molecular mechanisms of renal injury

描述（由申请人提供）：无论病因如何，小管间质纤维化是终末期肾脏疾病发展的一个不良预后指标和常见的最终途径，最终导致肾组织破坏和肾功能不可逆丧失。随着新诊断的慢性肾脏疾病和ESRD患者的发病率不断上升，对潜在机制的复杂理解和对控制肾纤维化的新分子靶点的识别是开发新疗法以扭转这一令人不安趋势的基础。肾小管周围毛细血管丧失是进行性肾脏疾病的标志，其结果是血流量减少，限制了向肾脏的氧气输送，导致慢性小管间质缺氧。细胞适应缺氧的关键介质是缺氧诱导因子(HIF)-1和-2，碱性螺旋-环-螺旋转录因子，主要以其调节血管重塑、红细胞生成和能量代谢的能力而闻名。在这里，我们假设缺氧代表了肾脏疾病发生和进展的早期和初始事件，并且HIF信号的激活促进上皮到间充质转化（EMT）和肾纤维化。由于肾脏HIF-1和HIF-2的生物学功能似乎依赖于细胞类型，因此我们提出了研究，a)在体内细胞类型特异性背景下研究单个HIF转录因子在进行性肾脏疾病发病机制中的作用，b)旨在鉴定相关的HIF调控基因和信号通路。具体来说，我们提出的研究包括：a)与Cre-loxP介导的重组相结合的进行性肾脏疾病动物模型，以实现HIF-1a和HIF-2a的细胞型特异性失活；b)研究特异性HIF靶基因及其在体外和体内EMT和纤维形成中的作用；c)基因调控研究；d)利用最先进的基因表达和启动子阵列来识别相关HIF靶基因的研究。总的来说，这笔拨款旨在建立一个研究项目，研究HIF激活对肾脏疾病发生和进展中至关重要的基因表达和信号网络的影响。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平衡的治疗，以阻止肾纤维化的进展。公共卫生相关性本资助研究低氧环境在慢性肾脏疾病进展中的作用。主要焦点是通过缺氧诱导因子（HIF）途径的信号传导。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.