PATHOPHYSIOLOGY OF RECESSIVE POLYCYSTIC KIDNEY DISEASE

凯斯西储大学（CWRU）多囊肾病跨学科研究中心的总体目标是吸引跨学科研究人员的合作伙伴，他们将使用互补和综合的方法来研究常染色体隐性多囊肾病（ARPKD）的分子和细胞病理生理学。ARPKD的发病率为1:10 000至1:40 000，新生儿死亡率为40-65%，约占儿童终末期肾病的5%。除了终末期肾病治疗和旨在治疗进行性门静脉高压并发症的姑息性措施外，对于ARPKD的进行性肾囊肿形成和扩大或进行性胆道扩张和纤维化没有已知的治疗方法。因此，该中心的总体目标是支持旨在描述疾病过程基本方面的科学研究，这些研究将转化为ARPKD预防和/或治疗策略的设计。该中心的一个辅助目标是吸引新的科学专业知识来研究多囊肾病。为了实现该中心的既定目标，该项目涉及来自CWRU儿科，遗传学和生理与生物物理系的跨学科研究团队。三个项目，三个核心，两个试点和可行性研究被科学地整合到一个总体方案中，直接遵循当前对ARPKD分子和细胞病理生理的理解。项目1，“上皮生长因子在ARPKD中的错误定位”重点关注介导上皮细胞异常增殖的关键过程。项目2，“ARPKD中收集小管离子转运改变”，重点研究介导小管液分泌改变的关键离子转运过程的异常。项目3，“ARPKD的药理和遗传治疗”是一个转化项目，旨在开发针对疾病发生和进展关键过程的治疗策略。为了支持科学项目，行政核心将协调中心的活动，并特别关注最大限度地提高中心调查员的科学互动，同时监测和批判性地评估科学过程，并鼓励多囊肾病相关领域的新研究。转基因和动物资源核心将利用最先进的分子遗传技术促进中心所有项目的全动物实验方法。细胞培养中心将为拟议的研究提供和维持来自人类和小鼠对照和囊肾的原代细胞和细胞系。虽然主要集中在ARPKD的分子和细胞病理生理上，但该中心开发的许多基础知识和许多治疗策略也将与常染色体显性多囊肾病的研究和治疗相关。

OVERALL DESCRIPTION (Taken directly from the application) The overall objective for the development of an Interdisciplinary Center for Polycystic Kidney Disease Research at Case Western Reserve University (CWRU) is to attract a partnership of interdisciplinary research among investigators who will use complementary and integrated approaches to study the molecular and cellular pathophysiology of autosomal recessive polycystic kidney disease (ARPKD). ARPKD has an incidence of 1: 10,000 to 1: 40,000, has a mortality of 40-65% in the newborn period, and accounts for approximately 5% of all end-stage renal disease in children. Other than end-stage renal disease therapy and palliative measures designed to treat the complications of progressive portal hypertension, there is no known therapy for progressive renal cyst formation and enlargement or progressive biliary ectasia and fibrosis in ARPKD. Therefore the overall goal of the Center is to support scientific investigation directed at delineating the fundamental aspects of the disease process which will translate into the design of preventative and/or curative strategies for ARPKD. An ancillary objective of the Center is to attract new scientific expertise to the study of polycystic kidney disease. To achieve the stated objectives of the Center, the program involves a interdisciplinary research team drawn from the Departments of Pediatrics, Genetics, and Physiology & Biophysics at CWRU. The three Projects, three Cores, and two Pilot and Feasibility studies are scientifically integrated into an overall scheme which follows directly from current understanding of the molecular and cellular pathophysiology of ARPKD. Project 1, "Epithelial Growth Factor Mislocalization in ARPKD" focuses on a key process mediating abnormal epithelial cell proliferation. Project 2, "Altered Collecting Tubule Ion Transport in ARPKD" focuses on abnormalities in key ion transport processes which mediate altered tubular fluid secretion. Project 3, "Pharmacological and Genetic Therapy of ARPKD" is a translational project to develop therapeutic strategies which target key processes operative in the development and progression of disease. To support the scientific program, an Administrative Core will coordinate Center activities and specifically focus on maximizing scientific interactions of Center Investigators while monitoring and critically evaluating scientific process and encouraging new research in polycystic kidney disease-related areas. A Transgenic & Animal Resource Core will facilitate whole animal experimental approaches for all projects of the Center using state-of-the-art molecular genetic technology. A Cell Culture Core will provide and maintain primary cells and cell lines from human and murine control and cystic kidneys for the proposed studies. Though largely focused on the molecular and cellular pathophysiology of ARPKD, much of the basic knowledge and many of the treatment strategies developed by the Center will also have relevance to the study and treatment of autosomal dominant polycystic kidney disease.