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州医学院建立一个跨学科的儿童肾病卓越研究中心（RCEPN），以阐明儿童肾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疗法以预防儿科年龄组疾病的发生和进展至关重要。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，因此将实验室转移到床边的方法具有很大的前景。（Avner，E.D. 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1月和2日）。肾脏疾病是婴儿、儿童和青少年患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，通常与已知或疑似基因突变相关。因此，本申请的主要项目集中在多囊肾病的病因学和进展中正常和异常肾发育生物学的遗传和细胞基础上。儿童获得性肾脏疾病的主要原因涉及肾小球损伤，随后肾血管，血流动力学和自动调节功能衰竭的改变。由此产生的超滤损伤是糖尿病肾病、局灶节段性硬化性肾小球肾炎、高血压和导致肾单位损失的任何原发性肾脏疾病中疾病进展和肾小管间质纤维化的主要原因。因此，RCEPN的另一个主要项目关注肾小球损伤和进行性肾小管间质纤维化中肾血流动力学改变的遗传和代谢决定因素。有趣的是，这两个不同的领域可能有共同的病理生理联系，通过改变肾代谢的花生四烯酸。生物化学和质谱核心和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人池中选择了四个优秀的申请。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具体方面，以及结构性肾病和糖尿病肾病的遗传调节和生化基础。适当关注儿童肾脏疾病将减少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过分。由于对大多数儿童肾脏疾病的基本分子和细胞机制知之甚少，因此RCEPN的建立特别及时。此外，进展为ESRD通常发生在原发性疾病过程被认为得到充分治疗时。因此，这两个拟议的RCEPN项目的明确目标是开发预防或调节这种进展的疗法。

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.