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Mechanisms of ADPKD cystogenesis

ADPKD 囊肿发生机制

基本信息

批准号：
9886234
负责人：
Gabriele Luca GUSELLA
金额：
$ 38.14万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-05 至 2021-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9886234
关键词：
Ablation Address Affect Architecture Autosomal Dominant Polycystic Kidney Bilateral Cell Proliferation Cell physiology Cells Characteristics Cilia Clinical Code Complex Cues Cyst Cystic Kidney Diseases Cystic kidney Cytogenetics Data Defect Development Dilatation - action Disease Disease Progression Duct (organ) structure ECM receptor End stage renal failure Epidermal Growth Factor Receptor Epithelial Epithelium Event Extracellular Matrix Focal Adhesions Gene Mutation Genes Genetic Genetic Models Germ-Line Mutation Growth Factor Receptors Impairment In Vitro Incidence Individual Integrin Inhibition Integrins Investigation Kidney Life Liquid substance Maintenance Mechanical Stimulation Mediator of activation protein Membrane Mendelian disorder Modeling Molecular Multiprotein Complexes Mus Nature Organ PKD1 gene PKD2 gene PKD2 protein Pathogenesis Pathway interactions Pharmacology Phenotype Prevention Process Protein Analysis Proteins Recycling Renal tubule structure Role Septate Severity of illness Signal Pathway Signal Transduction Testing Work cohesion comparative effective therapy experimental study extracellular genetic approach in vivo insight knock-down migration mouse model mutant nephrogenesis new therapeutic target polycystic kidney disease 1 protein preservation public health relevance receptor response small molecule small molecule inhibitor therapeutic target trafficking

项目摘要

DESCRIPTION (provided by applicant): Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a common life threatening disease characterized by progressive renal tubules dilatation, bilateral formation and expansion of multiple septate fluid-filled cysts that increasinly compress the renal parenchyma, thus altering the kidney architecture and gradually impairing organ function. To date there is no cure for ADPKD, which remains a main cause of end stage renal disease. Mechanisms underlying ADPKD pathogenesis are complex and not completely understood. The disease is caused by germline mutations in the PKD1 or PKD2 genes, which code for polycystin-1 (PC1) or polycystin-2 (PC2), respectively. PC1 and PC2 intersect in various signaling pathways that converge on largely overlapping clinical manifestations. In recent years, the importance of the cilium in renal development has prompted intense investigation of the different ciliary pathways involved in cytogenesis. However, the cilia hypothesis alone is insufficient to explain the more severe cytogenetic phenotypes associated with the loss of polycystins. Cystogenic events may occur that are independent of or preceding ciliary defects, although the nature of these early triggers remains unclear. Alteration of the extracellular matrix (ECM) has long been recognized as a distinctive feature of ADPKD epithelia, and the cystogenic process is associated with increased expression of integrins. Our previous work has shown the important role of integrin-α2β1 in the survival of PC1 knockdown cells. We recently showed that integrin-β1 is a previously unrecognized key mediator of cystic pathogenesis. The working hypothesis of this application is that ECM-Integrin-PC1 interactions are important in the cystic pathways of both ciliary and non-ciliary origin. This hypothesis will b tested both in vitro and in vivo. Specifically, we will determine how Integrin-β1 functions are affected by PC1 through the comparative analysis of the proteins that participate in the integrin-β1 activation pathway in normal and cystic cells, and will determine the role of integrin-β1 in te trafficking and cross-activation of the EGF receptor pathway in cell depleted of PC1. To test the role of integrin-β1 in renal cytogenesis from ciliary defects we will analyze the effects of the deletion of integrin-β1 in genetic models of renal cystic disease that allow the conditional deletion of Pkd1, IFT20, and IFT88. Finally, we will examine the function of integrin-β1 on disease progression and the possibility to ameliorate the cystic phenotype using a small molecule to target integrin-α2β1. The results of these studies will provide insights on the function of integrin-β1 in ADPKD pathogenesis and whether cystogenic mechanisms of different genetic origin may converge onto integrin-β1 signaling pathway. Importantly, this work will determine and whether the integrin pathway can be pharmacologically targeted to slow the progression of ADPKD.

描述(申请人提供)：常染色体显性遗传性多囊肾疾病(ADPKD)是一种常见的危及生命的疾病，其特征是进行性肾小管扩张，双侧形成和扩大多个分隔的充满液体的囊肿，增加对肾实质的压缩，从而改变肾脏结构并逐渐损害器官功能。到目前为止，ADPKD还没有治愈的方法，它仍然是终末期肾脏疾病的主要原因。ADPKD发病机制复杂，目前尚不完全清楚。这种疾病是由PKD1或PKD2基因的胚系突变引起的，这两个基因分别编码多囊蛋白-1(PC1)或多囊蛋白-2(PC2)。PC1和PC2在不同的信号通路中相交，这些信号通路在很大程度上重叠了临床表现。近年来，纤毛在肾脏发育中的重要性促使人们对参与细胞发生的不同纤毛途径进行了深入的研究。然而，纤毛假说本身不足以解释与多囊蛋白丢失相关的更严重的细胞遗传学表型。虽然这些早期触发因素的性质尚不清楚，但可能发生独立于或先于睫状体缺陷的成囊事件。细胞外基质(ECM)的改变一直被认为是ADPKD上皮细胞的一个显著特征，而囊变过程与整合素的表达增加有关。我们以前的工作已经证明了整合素-α2β1在PC1基因敲除细胞存活中的重要作用。我们最近发现整合素-β1是以前未知的囊性病变的关键介质。这一应用的工作假设是，ECM-整合素-PC1相互作用在睫状囊和非纤毛起源的囊性通路中都是重要的。这一假设将在体外和体内得到验证。具体地说，我们将通过对正常细胞和囊性细胞中参与整合素-β1激活途径的蛋白质的比较分析来确定整合素-β1的功能是如何受到PC1的影响的，并将确定整合素-β1在PC 1缺失的细胞中的TE转运和EGFR途径交叉激活中的作用。为了测试整合素-β1在纤毛缺陷引起的肾脏细胞发生中的作用，我们将分析整合素-β1的缺失在肾囊性疾病遗传模型中的作用，该遗传模型允许有条件地缺失PKD1IFT20和IFT88。最后，我们将研究整合素-β1在疾病进展中的作用，以及利用小分子靶向整合素-α2β1改善囊性表型的可能性。这些研究结果将为探讨整合素-β1在ADPKD发病机制中的作用以及不同遗传来源的囊变机制是否可能汇聚为整合素-β1信号通路提供依据。重要的是，这项工作将确定整合素途径是否具有药理学靶向性，以减缓ADPKD的进展。