Model of Congenital Obstructive Nephropathy-Biomarker & Therapeutic Development

描述（由申请人提供）：本项目的广泛、长期目标是阐明先天性梗阻性肾病的有效治疗干预和生物标志物。先天性梗阻性肾病是儿童慢性肾衰竭的主要原因，仅在美国，终末期肾衰竭估计每年花费150亿美元。尽管手术干预是先天性尿路梗阻的标准治疗，但大多数患者发展为慢性肾衰竭，约一半仍进展为终末期肾衰竭。这些观察结果突出了一个事实，即一些诊断，治疗和预后的困惑仍然存在于先天性梗阻性肾病的管理。我们已经鉴定出一种新的突变小鼠品系，命名为megabladder的mgb，它在子宫内出现明显的尿路梗阻症状，导致出生后发生输尿管积水和进行性肾功能衰竭。这个项目的长期目标是利用mgb小鼠模型来确定有效的生物标志物和治疗策略，用于早期阻塞性肾病的分类和管理。在具体目标1中，我们建议利用各种免疫组织化学和分子方法来完成表征的病理生理变化观察到的肾的mgb小鼠。我们实验室最近的研究表明，通过皮肤膀胱造口术可以挽救一定比例的mgb小鼠免于濒临死亡。基于这一观察结果，具体目标2将检查多种治疗策略的有效性，这些治疗策略旨在增强我们在mgb小鼠中的手术方法。最后，如具体目标3所述，在mgb小鼠中观察到的肾衰竭的逐渐进展为生物标志物的鉴定和表征提供了一个新的平台，该生物标志物可有效预测进行性肾损伤的过程，并鉴定需要更积极的连续治疗干预的个体。总之，mgb小鼠模型为我们提供了一个新的机会来研究与慢性肾功能衰竭发展相关的分子途径，也为生物标志物的开发和旨在改善这些动物中观察到的病理生理变化的手术和治疗策略的评估提供了一个平台。完成本提案中概述的研究将有助于我们诊断和治疗患有肾脏疾病的儿童和成人。 公共卫生相关性：先天性梗阻性肾病，即在子宫内时因尿流受阻而导致的肾损伤，是儿童长期肾衰竭的主要原因。尽管在出生后进行了手术来纠正堵塞，但大多数儿童会发生进行性肾损伤，导致生活质量低下，并经常过早死亡。我们已经开发了一种模拟先天性梗阻性肾病的小鼠模型。这将使我们能够在手术之外开发新的治疗方法，并找到新的标记物，告诉我们哪些儿童需要更多的手术来治疗他们的肾脏。

DESCRIPTION (provided by applicant): The broad, long-term objectives of this project are to elucidate effective therapeutic interventions and biomarkers for congenital obstructive nephropathy. Congenital obstructive nephropathy is the leading cause of chronic renal failure in children, with end-stage renal failure estimated to cost 15 billion dollars annually in the United States alone. Despite surgical intervention, the standard of care for congenital urinary obstruction, the majority of patients develop chronic renal failure and about half still progress to end stage renal failure. These observations highlight the fact that a number of diagnostic, therapeutic and prognostic quandaries still exist in the management of congenital obstructive nephropathy. We have identified a novel mutant mouse line, designated mgb for megabladder, that develops overt signs of urinary tract obstruction in utero resulting in the development of hydroureteronephrosis and progressive renal failure following birth. The long-term objectives of this project are to utilize the mgb mouse model to identify effective biomarkers and therapeutic strategies for the classification and management of obstructive nephropathy early in life. In Specific Aim 1, we propose to utilize a variety of immunohistochemical and molecular approaches to complete characterization of the pathophysiological changes observed in the kidneys of mgb mice. Recent studies in our lab indicate that a percentage of mgb mice can be rescued from imminent death by performing cutaneous vesicostomy. Based upon this observation, Specific Aim 2 will examine the efficacy of multiple therapeutic strategies designed to augment our surgical approach in mgb mice. Finally, as outlined in Specific Aim 3, the gradual progression of renal failure observed in mgb mice provides a novel platform for the identification and characterization of biomarkers that effectively predict the course of progressive kidney injury and identify individuals that are in need of more aggressive adjunctive therapeutic interventions. In summary, the mgb mouse model provides us with a novel opportunity to examine the molecular pathways associated with the development of chronic renal failure, as well as a platform for biomarker development and the assessment of surgical and therapeutic strategies designed to ameliorate the pathophysiological changes observed in these animals. Completion of the studies outlined in this proposal will help us diagnose and treat children and adults with kidney disease. PUBLIC HEALTH RELEVANCE: Congenital obstructive nephropathy, kidney damage resulting from blockage of urine flow while still in the womb, is the leading cause of long-term kidney failure in children. Despite surgery to correct the blockage after birth, most children develop progressive kidney injury, leading to a poor quality of life and often early death. We have developed a mouse model that mimics congenital obstructive nephropathy. This will allow us to develop new therapies in addition to surgery and to find new markers that will tell us which children would need more than surgery alone to treat their kidneys.