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（由申请人提供）：本次竞争性更新的目的是继续我们正在进行的研究，了解骨膜素对 PKD 肾囊肿扩大和纤维化的作用，并确定整合素连接激酶 (ILK)（一种受骨膜素结合调节的激酶）是否αV-整合素是 PKD 的药理学靶标，Periostin 以前称为成骨细胞特异性因子 2 (OSF-2)，是一种新近被认可的药物。基质细胞蛋白的成员，还包括血小板反应蛋白、骨桥蛋白、ßig-H3、SPARC 和结缔组织生长因子。在涉及机械应力条件的组织中表达，例如牙周膜、骨膜和心脏瓣膜，并分泌到细胞外基质中。 (ECM) 心脏、皮肤和其他组织急性损伤后，它直接与 ECM 成分（包括胶原蛋白和纤连蛋白）相互作用，并促进胶原蛋白生成。骨膜素的异常表达与细胞增殖、存活和组织血管生成相关途径的激活有关，我们的实验室发现骨膜素是最常见的表达途径之一。与正常人肾细胞相比，人 ADPKD 细胞中高度过表达的基因在原位 ADPKD 肾囊肿和重组骨膜蛋白附近的 ECM 中积聚。促进 ADPKD 囊肿上皮细胞的增殖。在 ARPKD 患者和多种 PKD 动物模型的肾脏中，Periostin 也过度表达，这表明无论潜在的 Periostin 基因突变如何，periostin 的异常表达都是 PKD 的普遍特征。 pcy/pcy 小鼠是一种缓慢进行性 PKD 模型，导致肾脏重量/体重、囊肿数量和囊肿面积、增殖细胞和 mTOR 急剧下降间质纤维化也减少，肾功能得到改善，小鼠的存活率显着增加，这表明骨膜蛋白及其信号通路可能是 ADPKD 的潜在治疗靶点，我们发现骨膜蛋白和可能的其他基质细胞蛋白与 aV 结合。 -整合素并刺激ILK，促进囊性细胞的增殖和存活以及导致纤维化的ECM分子的异常表达在目标1中，我们将确定骨膜蛋白在收集中是否过度表达。导管刺激 ILK 信号传导、囊肿生长和间质 Pkd1RC/RC 低等态小鼠和 pcy/pcy 小鼠的纤维化在目标 2 中，我们将确定 ILK 的遗传缺失是否会减缓 Pkd1 突变体和 pcy/pcy 小鼠中的 PKD 进展。在目标 3 中，我们将描述 ILK 下游的信号通路。骨膜素诱导人 ADPKD 细胞的增殖、存活和基质产生在目标 4 中，我们将确定 aVß3 整合素是否具有药理抑制作用。 ILK 可以减缓或阻止 Pkd1 突变小鼠和 pcy/pcy 小鼠的 PKD 进展。