Novel Therapeutic Strategies for PKD

多囊肾病（PKD）在美国影响大于或等于500，000名患者，在全世界影响大于或等于600万名患者，但唯一的“治疗”形式是通过透析或移植进行肾脏替代。最常见和最重要的肾脏畸形是遗传性的。常染色体显性（AD）PKD的发病率大于或等于1：500，占所有透析患者的7%以上，而常染色体隐性（AR）PKD的发病率大于或等于1：20，000，新生儿期死亡率大于或等于50%，占儿童终末期肾衰竭病例的5%以上。该计划项目的总体目标是建立一个多学科团队，开发和应用对多囊肾疾病的分子细胞和生理基础的新认识，以开发新的，合理的治疗方法。最终目标是开发预防性和/或治疗性治疗，以减缓疾病进展，从而提供目前缺乏的治疗。来自医学系、儿科系、泌尿科系、基因治疗研究所和癌症中心的医学科学家已经建立了一个临界质量，采用多方面的方法研究肾脏形态发生和畸形，从分子、细胞、生理、遗传和临床方法，从而构成了一个综合的基础和转化方案。这五个项目和两个核心将是高度互动的，并科学地整合在一个方案中，该方案侧重于通过磷酸化调节PKD 1基因产物多囊蛋白的功能，项目1;多囊蛋白-1在控制肾形态发生中的作用，项目2; WT 1靶蛋白“发芽”在囊性肾发育中的作用，项目3;在ARPKD，项目4中钠和钾转运的分析;和在ARPKD，项目5中顶端EGF受体信号传导的功能后果。该核心将提供和开发病毒载体、肾细胞系和器官培养物以及转基因、基因敲除和其他小鼠模型。此外，该核心将集中服务 和功能测定，包括粘附、迁移、3D凝胶小管形成、胚胎小鼠肾器官培养和显微注射。这些综合研究将增加我们对多囊肾疾病的潜在生物学的理解，足以导致在体外人细胞和小鼠器官培养中以及通过小分子和/或基因治疗策略在体内测试治疗方法。

Polycystic kidney diseases (PKD) affect greater than or equal too 500,000 patients in the US and > 6 million worldwide, but the only form of "therapy" is renal replacement by dialysis or transplantation. The most common and important renal malformations are genetic in origin. Autosomal dominant (AD)PKD has an incidence of greater than or equal too1:500 and accounts for greater than or equal too 7% of all patients on dialysis, while autosomal recessive (AR)PKD) has an incidence of greater than or equal too 1: 20,000 with a mortality of greater than or equal too50% in the newborn period and accounts for >5% cases of endstage renal failure in children. The overall goal of this program project is to establish a multidisciplinary team to develop and apply the expanding new understanding of the molecular cellular and physiological basis of polycystic kidney diseases to the development of novel, rational therapeutic approaches. The ultimate goal is to develop preventive and/or therapeutic treatments to slow disease progression and thus offer treatment that is at present lacking. Medical scientists from the Departments of Medicine, Pediatrics, Urology, Gene Therapy Institute and Cancer Center have established a critical mass with a multifaceted approach to study renal morphogenesis and malformations ranging from molecular, cellular, physiological, genetic and clinical approaches, thus constituting a combined basic and translational program. The five projects and two cores will be highly interactive and are scientifically integrated in a scheme that focuses on the regulation of the function of the PKD 1 gene product, polycystin by phosphorylation, Project 1; the role of polycystin- 1 in the control of renal morphogenesis, Project 2; the role of the WTl-target protein "sprouty" in cystic kidney devlopment, Project 3; the analysis of sodium and potassium transport in ARPKD, project 4; and the functional consequences of apical EGF receptor signalling in ARPKD, Project 5. The Core will provide and develop viral vectors, renal cell lines and organ cultures as well as transgenic, knock-out and other mouse models In addition, this Core will centralize services and functional assays including adhesion, migration, 3D gel tubulogenesis, embryonic mouse kidney organ culture and microinjections. These integrated studies will increase our understanding of the underlying biology of polycystic kidney diseases sufficiently to lead to testing of therapeutic approaches in human cells in vitro and mice in organ culture and in vivo by small molecule and/or gene therapy strategies.