The role of Macrophage Delivered WNT Signaling in kidney injury and repair

描述（由申请人提供）：慢性肾脏疾病是影响数百万人的公共卫生流行病。对医疗保健、我们的社区和个人造成的损失是深远的。慢性肾脏疾病，以慢性炎症、实质细胞损失和纤维化为特征。然而，当肾脏受伤时，它有巨大的恢复能力。了解正常恢复的机制以及它们与肾脏进行性炎症的区别将导致新的治疗方法。我们一直在研究巨噬细胞的作用，巨噬细胞是免疫系统募集到肾脏的细胞，在调节肾脏的正常修复过程和指导纤维化的发展中，这是肾衰竭的前兆。我们已经发现，规范的WNT细胞间信号通路，调节细胞存活、分化、迁移、增殖和凋亡，曾经被认为仅限于胚胎发育和癌症的旁分泌细胞通讯，在肾脏修复和肾脏纤维化过程中是活跃的。我们的中心假设得到了大量初步数据的支持，即肾脏中的炎性巨噬细胞释放可溶性配体（WNT），通过旁分泌细胞上的WNT受体发出信号，这种信号传导在介导肾脏修复中起重要作用。然而，当损伤持续时，炎性巨噬细胞发出的WNT信号支持间质成纤维细胞的增加，并指导瘢痕组织的产生。在AIM 1中，我们将重点关注损伤后的正常肾脏修复。我们将研究炎性巨噬细胞的确切作用，并剖析上皮细胞在将WNT信号传递给肾脏邻近细胞中的支持作用。我们将在小鼠中使用遗传学方法研究：体内巨噬细胞条件消融对WNT信号的影响；WNT受体frzzled4、Lrp-5、Lrp-6在肾脏修复中的作用；以及巨噬细胞Wnt-7b或Wnt配体释放蛋白Wntless在体内修复中的作用。我们将使用可溶性WNT信号调节剂来影响肾脏的修复。在AIM 2中，我们将重点关注巨噬细胞传递的WNT信号在肾脏纤维化进展中的作用。利用遗传学方法，我们将在小鼠中研究成纤维细胞WNT受体frizzled7的作用；巨噬细胞Wnt配体释放蛋白Wntless；以及成纤维细胞中的转录调节因子-连环蛋白对体内纤维化进展的影响。我们将测试可溶性WNT调节剂（包括Dickkopf-1和-2）对纤维化进展的影响。相关性：这些研究的总体目的是确定巨噬细胞，特别是上皮细胞在正常肾脏修复中的典型WNT信号的作用，以及纤维化发展中的成纤维细胞。通过了解巨噬细胞调节肾脏损伤和修复的机制，我们将开发新的治疗模式，支持正常修复，并抵消人类纤维化。

DESCRIPTION (provided by applicant): Chronic kidney disease is a public health epidemic affecting millions. The toll to health care, our communities and to individuals is profound. Chronic kidney disease and is characterized by chronic inflammation, parenchymal cell loss and fibrosis. However the kidney when injured has enormous capacity for recovery. Understanding the mechanisms of normal recovery and how they differ from progressive inflammation in the kidney will lead to new therapies. We have been studying the role of macrophages, cells of the immune system recruited to the kidney, in regulating the normal repair process in the kidney and in directing the development of fibrosis, which is a harbinger of kidney failure. We have discovered that the Canonical WNT cell-to-cell signaling pathway, that regulates cell survival, differentiation, migration, proliferation and apoptosis, once thought to be restricted to paracrine cell communications of embryonic development and cancer, is active during kidney repair and also during kidney fibrosis. Our central hypothesis supported by extensive preliminary data is that inflammatory macrophages in the kidney release soluble ligands (WNTs) that signal via WNT receptors on paracrine cells and that this signaling plays an important role in mediating kidney repair. However when injury is persistent, WNT signaling from inflammatory macrophages supports the increase in interstitial fibroblasts and directs generation of scar tissue. In AIM 1 we will focus on normal kidney repair following injury. We will examine the precise role of inflammatory macrophages and dissect a supporting role from epithelial cells in delivering WNT signals to neighboring cells of the kidney. We will use genetic approaches in the mouse to study: the effect of conditional ablation of macrophages in vivo on WNT signaling; the importance of WNT receptors Frizzled-4, Lrp-5 and Lrp-6 in kidney repair; and the role of macrophage Wnt-7b or the Wnt ligand release protein Wntless in vivo, in repair. We will administer soluble modulators of WNT signaling to affect repair of the kidney. In AIM 2 we will focus Macrophage delivered WNT signaling on the progression of fibrosis in the kidney. Using genetic approaches in the mouse we will study the role of fibroblast WNT receptor Frizzled-7; the macrophage Wnt ligand release protein Wntless; and the transcriptional regulator ¿-catenin in fibroblasts, on fibrosis progression in vivo. We will test the impact of soluble WNT modulators including Dickkopf-1 and -2 on fibrosis progression. Relevance: The overall purpose of these studies is to determine the roles of Canonical WNT signaling from macrophages, particularly to epithelial cells in normal kidney repair, but also to fibroblasts in the development of fibrosis. By understanding the mechanisms by which macrophages regulate injury and repair in the kidney we will develop new therapeutic paradigms that support normal repair, and counteract fibrosis in humans.