Integrative Biology of Childhood Kidney Disease

总体描述(由申请人提供)： 我们建议在威斯康星医学院建立一个跨学科的儿科肾病卓越研究中心(RCEPN)，以描述儿童肾脏疾病及其进展的潜在遗传和细胞原因。这些数据对于开发特定的治疗方法以防止儿科年龄组疾病的开始和发展至关重要。由于儿童肾脏疾病通常是成人肾脏和心血管并发症的先兆，将板凳移植到床边的方法有很大的前景。(Avner，E.D.和Kliegman，R.M.：临床实践的科学基础，第一部分和第二部分，北美儿科诊所53：559-806；807-1051；2006年第一卷和第二卷)。肾脏疾病是导致婴儿、儿童和青春期疾病和死亡的主要原因。来自美国和欧洲的总体登记数据表明，大约50%的儿童患有结构性肾脏异常，通常与已知或可疑的基因突变有关。因此，目前应用的一个主要项目集中在正常和异常肾脏发育生物学在多囊性肾脏疾病的病因和进展中的遗传学和细胞学基础上。儿童获得性肾脏疾病的主要原因包括肾小球损伤以及随后的肾血管、血流动力学和自我调节功能障碍。由此产生的高滤过损伤是糖尿病肾病、局灶性节段性硬化性肾小球肾炎、高血压和任何导致肾单位丢失的原发肾脏疾病的主要疾病进展和肾间质纤维化的主要原因。因此，RCEPN的另一个主要项目集中在肾小球损伤和进行性肾小管间质纤维化中肾脏血流动力学改变的遗传和代谢决定因素。有趣的是，这两个不同的区域可能通过改变花生四烯酸的肾脏代谢而具有共同的病理生理联系。生化和质谱学核心以及基因组动物和载体核心直接支持这些项目，并支持一个强大的试点和可行性(P&F)计划，该计划从令人印象深刻的初始申请者库中挑选了四个优秀的申请。这些试点和可行性项目涉及急性缺血性损伤的遗传和细胞生物学的特定方面，以及结构性肾脏疾病和糖尿病肾病的遗传调控和生化基础。适当关注儿童肾脏疾病将减轻成人肾脏疾病的负担及其伴随的发病率和死亡率，这一点怎么强调都不为过。由于大多数儿童肾脏疾病的基本分子和细胞机制尚不清楚，因此建立这一RCEPN特别及时。此外，当原发病过程被认为得到了适当的治疗时，通常会发生向终末期肾病的进展。因此，这个拟议的RCEPN的两个项目的一个明确目标是开发预防或调节这种进展的治疗方法。

DESCRIPTION, OVERALL (provided by applicant): We propose to develop an interdisciplinary Research Center of Excellence in Pediatric Nephrology (RCEPN) at the Medical College of Wisconsin to delineate the underlying genetic and cellular causes of childhood renal disease and its progression. Such data are critical in developing specific therapies to prevent the initiation and progression of disease in the pediatric age group. Since childhood kidney disease is often a harbinger of renal and cardiovascular complications in adults, translational bench to bedside approaches have great promise. (Avner, E.D. and Kliegman, R.M.: Scientific Foundations of Clinical Practice, Part I and II, Pediatric Clinics of North America 53:559-806; 807-1051;2006 Vol I and 2). Kidney disease is a major cause of illness and death in infants, children and adolescence. Overall registry data from both the United States and Europe indicate that approximately 50% of all children have structural renal abnormalities, generally associated with known or suspected genetic mutations. Accordingly, a major project of the current application focuses on the genetic and cellular basis of normal and abnormal renal developmental biology in the etiology and progression of Polvcystic Kidney Disease. Major causes of acquired renal disease in childhood involve glomerular injury with subsequent alterations in renal vascular, hemodynamics and autoregulatory failure. The resultant hyperfiltration injury is a major cause of disease progression and tubulointerstitial fibrosis in diabetic nephropathy, focal segmental sclerosing glomerulonephritis, hypertension, and any primary renal disease which leads to nephron loss. Therefore, another major project of the RCEPN focuses on the genetic and metabolic determinants of altered renal hemodynamics in glomerular injury and progressive tubulointerstitial fibrosis. Interestingly, these two disparate areas may have common pathophysiological linkages through alterations in renal metabolism of arachidonic acid. The Biochemical and Mass Spectroscopy Core and the Genomic Animal and Vector Core directly support these projects, as well as supporting a robust pilot and feasibility (P & F) program which has selected four outstanding applications from an impressive initial applicant pool. These Pilot and Feasibility projects deal with specific aspects of the genetic and cellular biology of acute ischemic injury, and the genetic modulation and biochemical basis of structural renal disease and diabetic nephropathy. It cannot be overemphasized that appropriate focus on childhood renal disease will decrease the burden of adult renal disease with its attendant morbidity and mortality. Since the basic molecular and cellular mechanisms of the majority of pediatric kidney disorders are poorly understood, the establishment of this RCEPN is particularly timely. In addition, progression to ESRD often occurs when a primary disease processes has been thought to be adequately treated. Therefore, a clear aim of both projects of this proposed RCEPN is the development of therapies which prevent or modulate this progression.