Novel Therapeutic Strategies for PKD

多囊肾病(PKD)在美国影响超过50万患者，在全球范围内影响600万人，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。常染色体显性遗传性(AD)PKD的发病率大于等于1：500，占所有透析患者的比例大于或等于7%，而常染色体隐性遗传(AR)PKD的发病率大于或等于1：20,000，新生儿死亡率大于或等于50%，占儿童终末期肾功能衰竭的5%。该计划项目的总体目标是建立一个多学科团队，以发展和应用对多囊肾病分子细胞和生理基础的不断扩大的新理解，以开发新的、合理的治疗方法。最终目标是开发预防和/或治疗方法，以减缓疾病的发展，从而提供目前缺乏的治疗方法。来自内科、儿科、泌尿外科、基因治疗研究所和癌症中心的医学科学家建立了一个临界点，从分子、细胞、生理、遗传和临床等方面研究肾脏的形态发生和畸形，从而构成了一个基础和翻译相结合的计划。这五个项目和两个核心将高度互动，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基因产物多囊藻毒素的功能，项目1；多囊蛋白-1在控制肾脏形态发生中的作用，项目2；WT1靶蛋白“芽”在囊性肾脏发育中的作用，项目3；分析ARPKD中钠和钾的运输，项目4；以及ARPKD顶端EGF受体信号的功能后果，项目5。核心将提供和开发病毒载体、肾脏细胞系和器官培养以及转基因、基因敲除和其他小鼠模型。此外，该核心将集中服务 功能检测包括黏附、迁移、3D凝胶小管形成、胚胎小鼠肾器官培养和微量注射。这些综合研究将充分增加我们对多囊肾病的潜在生物学的了解，从而通过小分子和/或基因治疗策略在体外的人类细胞和器官培养的小鼠身上测试治疗方法。

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.