Hedgehog Signaling in Kidney Homeostasis and Repair

描述(由申请人提供)：急性和慢性肾脏损伤对美国人的健康造成严重的和日益严重的损害。肾脏在多种形式的急性损伤后具有令人印象深刻的自我修复能力，对这一过程的细胞和分子机制的深入了解将确定治疗人类肾衰竭的新的治疗方法。Hedgehog(HH)分泌信号分子家族的成员调节细胞的增殖、分化和组织模式。它们在肾脏形成过程中发挥着重要作用，在其他器官中作为组织再生的调节因子越来越受到重视。这项建议将调查刺猬配体在肾脏动态平衡和修复中的作用。两个HH配体在肾脏中表达，印度刺猬(IHH)和音速刺猬(Shh)，它们是由肾小管上皮细胞表达的。Hedgehog反应细胞位于肾间质内，与上皮细胞相邻。我们假设，在动态平衡期间，产生HH的上皮细胞和HH反应的间质细胞之间的串扰维持细胞分化，而肾脏损伤上调HH信号，触发组织修复，或者如果损伤正在进行，则导致不适应性间质纤维化。在目标1中，我们将在细胞水平上表征HH通路成分的表达，并检测急性损伤期间药物抑制HH信号是否导致肾上皮细胞再分化的延迟。在目标2中，我们使用药理学和遗传获得或功能丧失的方法来激活或抑制急性和慢性肾损伤期间的HH信号，以评估HH途径的调节是否可能代表一个新的治疗靶点。在目标3中，我们将使用周细胞培养模型来具体研究HH信号在肾脏中发挥作用的机制，并使用体内周细胞命运图来测试HH反应细胞在慢性损伤过程中是否扩张并分化为形成瘢痕的肌成纤维细胞。 公共卫生相关性：慢性肾脏疾病在我们老龄化人口中的流行日益增加，这是一个巨大的健康负担。由于大多数慢性肾病的最终共同途径是肾脏纤维化，逆转甚至减缓纤维化的治疗将产生巨大的临床影响。这些研究将探索一种名为Hedgehog的信号通路的作用。目前正在开发调节这一途径的药物，因此这些研究可能会确定此类药物在治疗肾脏纤维化方面的新用途。肾脏纤维化在美国和世界范围内仍是一个巨大的问题。

DESCRIPTION (provided by applicant): Acute and chronic kidney injury exacts a profound and growing toll on the health of Americans. The kidney possesses an impressive capacity to repair itself after many forms of acute injury, and a deeper understanding of the cellular and molecular mechanisms of this process will identify new therapeutic approaches to treat human suffereing from kidney failure. Members of the Hedgehog (Hh) family of secreted signaling molecules regulate cell proliferation, differentiation and tissue patterning. They play important roles during nephrogenesis and in other organs are increasingly appreciated as regulators of tissue regeneration. This proposal will investigate the role of hedgehog ligands in kidney homeostasis and repair. Two Hh ligands are expressed in kidney, Indian hedgehog (Ihh) and Sonic hedgehog (Shh), and these are expressed by tubular epithelial cells. Hedgehog responsive cells are located adjacent to epithelia, in the renal interstitium. We hypothesize that crosstalk between Hh-producing epithelia and Hh-responsive interstitial cells maintains cellular differentiation during homeostasis, whereas kidney injury upregulates Hh signaling triggering tissue repair, or if the injury is ongoing, resulting in maladaptive interstitial fibrosis. In Aim 1, we will characterize at the cellular level the expression of Hh pathway components, and examine whether pharmacologic inhibition of Hh signaling during acute injury results in a delay in the re-differentiation of renal epithelia. In Aim 2, we use pharmacologic and genetic gain or loss-of-function approaches to activate or inhibit Hh signaling during acute and chronic renal injury to assess whether modulation of the Hh pathway might represent a novel therapeutic target. In Aim 3, we will specifically address the mechanism by which Hh signals exert their effects in kidney using pericyte cell culture models and we employ in vivo pericyte fate mapping to test whether Hh-responsive cells expand and differente into scar forming myofibroblasts during chronic injury. PUBLIC HEALTH RELEVANCE: The increasing prevalence of chronic kidney disease in our aging population represents an enormous health burden. Because the final common pathway for most chronic nephropathies is renal fibrosis, therapies that reverse or even slow fibrosis would have tremendous clinical impact. These studies will explore the role of a signaling pathway called Hedgehog. Drugs are now being developed to modulate this pathway, so these studies might identify a new use for such drugs in treating kidney fibrosis which remains a tremendous problem in the United States and worldwide.