Role of Periostin in Polycystic Kidney Disease

骨膜素在多囊肾病中的作用

基本信息

批准号：
9125814
负责人：
DARREN P. WALLACE
金额：
$ 33.98万
依托单位：
UNIVERSITY OF KANSAS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-08-21 至 2019-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9125814
关键词：
Acute Adult Affect Age Animal Model Area Autosomal Dominant Polycystic Kidney Autosomal Recessive Polycystic Kidney Benign Binding Binding Proteins Body Weight Cell Adhesion Cell Proliferation Cell Survival Cell surface Cells Cilengitide Collagen Communication Complex Cyst Cystic Kidney Diseases Cystic kidney DNA Sequence Alteration Data Disease Duct (organ) structure Epithelial Cell Proliferation Epithelial Cells Extracellular Matrix FRAP1 gene Fibronectins Fibrosis Genes Genetic Goals Growth Health Heart Heart Valves Human In Situ Injury Integrin alphaV Integrins Investigation Kidney Kidney Failure Knock-out LIMS1 gene Laboratories Lead Link Liquid substance Longevity MADH2 gene MADH4 gene MRI Scans Measures Mechanical Stress Mediating Modeling Molecular Monitor Morphology Mus Mutant Strains Mice Names Neoplasms Nephrons Osteoblasts Other Genetics Pathway interactions Patients Periodontal Ligament Periosteum Phosphotransferases Polycystic Kidney Diseases Production Proliferating Proteins Proteomics Recombinants Renal function Ribosomal Protein S6 Kinase Role Signal Pathway Signal Transduction Skin Tamoxifen Testing Thrombospondins Tissue Survival Tissues Transgenic Mice Weight Wit angiogenesis beta catenin cancer therapy connective tissue growth factor fibrillogenesis glycogen synthase kinase 3 beta improved integrin-linked kinase interstitial kidney cell kinase inhibitor knock-down knockout gene member migration mutant novel osteopontin overexpression periostin scaffold small hairpin RNA small molecule inhibitor therapeutic target tumor growth

项目摘要

DESCRIPTION (provided by applicant): The purpose of this competitive renewal is to continue our ongoing investigation on the role of periostin on renal cyst enlargement and fibrosis in PKD and determine if integrin-linked kinase (ILK), a kinase regulated by periostin-binding to aV-integrins, is a pharmacological target for PKD. Periostin, previously named osteoblast- specific factor 2 (OSF-2), is a newly recognized member of matricellular proteins that also includes thrombospondins, osteopontin, ßig-H3, SPARC and connective tissue growth factors. Periostin is expressed in tissues involved in mechanical stress conditions, such as the periodontal ligaments, periosteum and cardiac valves and is secreted into the extracellular matrix (ECM) following acute injury to the heart, skin and other tissues. It directly interacts wit components of the ECM, including collagen and fibronectin, and promotes collagen fibrillogenesis to maintain tissue integrity. Aberrant expression of periostin is associated with fibrosis and tumor growth through activation of pathways involved in cell proliferation, survival and tissue angiogenesis. Periostin is not normally expressed in adult kidney. Our laboratory discovered that periostin was one of the most highly over-expressed genes in human ADPKD cells compared to normal human kidney cells. Periostin accumulates in the ECM adjacent to cysts of ADPKD kidneys in situ and recombinant periostin promotes proliferation of ADPKD cyst epithelial cells. Periostin is also overexpressed in the kidneys of ARPKD patients and several animal models of PKD, suggesting that aberrant expression of periostin is a general feature of PKD regardless of the underlying genetic mutation. Global gene knockout of periostin in pcy/pcy mice, a model of slowly progressive PKD, caused a dramatic decrease in kidney weight/body weight, cyst number and cystic area, proliferating cells and mTOR signaling. There was also reduced interstitial fibrosis, improved kidney function, and a significant increase in the survivalof the mice, suggesting that periostin and its signaling pathway may be potential therapeutic targets for ADPKD. We hypothesize that periostin and possibly other matricellular proteins bind to aV-integrins and stimulate ILK, promoting proliferation and survival of cystic cells and aberrant expression of ECM molecules leading to fibrosis. In Aim 1, we will determine if periostin overexpression in collecting ducts stimulates ILK signaling, cyst growth and interstitial fibrosis in Pkd1RC/RC hypomorphic mice and pcy/pcy mice. In aim 2, we will determine if genetic loss of ILK slows PKD progression in Pkd1 mutant and pcy/pcy mice. In Aim 3, we will delineate signaling pathways downstream of ILK for periostin-induced proliferation, survival and matrix production by human ADPKD cells. In Aim 4, we will determine if pharmacological inhibition of aVß3 integrin and ILK slows or halts PKD progression in Pkd1 mutant mice and pcy/pcy mice.

描述（由适用提供）：这种竞争性更新的目的是继续我们对PKD中肾脏囊肿增强和纤维化作用的作用进行持续的调查，并确定整联蛋白链接激酶（ILK）是否是一种由周期结合到AV-凝集素对AV-注视的激酶，是PKD的药物靶标。先前称为成骨细胞特异性因子2（OSF-2）的骨膜素是基质蛋白的新成员，它还包括血小板蛋白蛋白，骨桥蛋白，骨蛋白蛋白，ßig-H3，SPARC和结缔组织生长因子。骨膜素在涉及机械应力条件的组织中表达，例如牙周韧带，骨膜和心脏瓣膜，并在急性损伤心脏，皮肤和其他组织后分泌到细胞外基质（ECM）中。它直接相互作用ECM的机智成分，包括胶原蛋白和纤连蛋白，并促进胶原蛋白原纤维生成以维持组织完整性。周期素异常表达与纤维化和肿瘤生长有关，通过激活细胞增殖，生存和组织血管生成的途径。骨膜素通常在成年肾脏中不表达。我们的实验室发现，与正常的人类肾细胞相比，时期是人ADPKD细胞中最高表达的基因之一。骨膜素积聚在与ADPKD Kidneys囊肿相邻的ECM中，而重组周期促进了ADPKD囊肿上皮细胞的增殖。骨膜素在ARPKD患者和PKD的几种动物模型的儿童中也过表达，这表明erpectin的异常表达是PKD的一般特征，而不论基本的基因突变如何。 PCY/PCY小鼠的全球基因敲除（一种缓慢的进行性PKD模型）导致肾脏急剧下降，我们假设该周期和可能的其他材料蛋白与AV-积聚蛋白结合并刺激ILK，并促进了ECM Molecules促成ECM Molecules纤维化的囊肿和生存。在AIM 1中，我们将确定在收集管道中的过度表达是否刺激ILK信号传导，囊肿生长和间隙 PKD1RC/RC肌病中的纤维化和PCY/PCY小鼠。在AIM 2中，我们将确定ILK的遗传丧失是否会减慢PKD1突变体和PCY/PCY小鼠的PKD进展。在AIM 3中，我们将描述ILK下游的信号通路，以通过人ADPKD细胞产生周期诱导的增殖，存活和基质。在AIM 4中，我们将确定PKD1突变小鼠和PCY/PCY小鼠中AVß3整合蛋白和ILK的药物抑制是否会减慢或停止PKD进展。