Role of Periostin in Polycystic Kidney Disease

骨膜素在多囊肾病中的作用

• 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
• 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

 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（由申请方提供）：本次竞争性更新的目的是继续我们正在进行的关于骨膜蛋白在PKD中对肾囊肿增大和纤维化的作用的研究，并确定整合素相关激酶（ILK）（一种由骨膜蛋白与α V-整合素结合调节的激酶）是否是PKD的药理学靶点。骨膜蛋白（Periostin），以前称为成骨细胞特异性因子2（OSF-2），是一种新发现的基质细胞蛋白质，其还包括血小板反应蛋白、骨桥蛋白、β ig-H3、TGF β 1和结缔组织生长因子。骨膜蛋白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，并且在心脏、皮肤和其他组织急性损伤后分泌到细胞外基质（ECM）中。它直接与ECM的组分相互作用，包括胶原蛋白和纤连蛋白，并促进胶原蛋白原纤维形成以保持组织完整性。骨膜蛋白的异常表达通过激活参与细胞增殖、存活和组织血管生成的途径与纤维化和肿瘤生长相关。骨膜蛋白在成人肾脏中不正常表达。我们的实验室发现，与正常人肾细胞相比，骨膜蛋白是人ADPKD细胞中最高度过表达的基因之一。骨膜蛋白在ADPKD肾囊肿附近的ECM中原位积累，重组骨膜蛋白促进ADPKD囊肿上皮细胞的增殖。骨膜蛋白在ARPKD患者的肾脏和PKD的几种动物模型中也过表达，表明骨膜蛋白的异常表达是PKD的一般特征，而不管潜在的基因突变如何。在pcy/pcy小鼠（缓慢进行性PKD的模型）中，骨膜蛋白的整体基因敲除引起肾重量/体重、囊肿数量和囊肿面积、增殖细胞和mTOR信号传导的急剧减少。间质纤维化减少，肾功能改善，小鼠存活率显著增加，表明骨膜蛋白及其信号通路可能是ADPKD的潜在治疗靶点。我们假设骨膜蛋白和可能的其他基质细胞蛋白结合α V-整联蛋白并刺激ILK，促进囊性细胞的增殖和存活以及ECM分子的异常表达，导致纤维化。在目标1中，我们将确定在集合管中骨膜蛋白过表达是否刺激ILK信号传导、囊肿生长和间质增生。 在Pkd 1 RC/RC低形态小鼠和pcy/pcy小鼠中的纤维化。在目标2中，我们将确定在Pkd 1突变和pcy/pcy小鼠中ILK的遗传缺失是否减缓PKD进展。在目标3中，我们将描绘ILK下游的信号通路，用于人ADPKD细胞的骨膜蛋白诱导的增殖、存活和基质产生。在目的4中，我们将确定α V β 3整联蛋白和ILK的药理学抑制是否减缓或停止Pkd 1突变小鼠和pcy/pcy小鼠中的PKD进展。