A genetic model of vesicoureteral reflux and reflux nephropathy

描述（由申请人提供）：膀胱输尿管反流（VUR-尿液从膀胱回流到输尿管）是儿童最常见的泌尿生殖系统异常，反流性肾病是儿童慢性肾衰竭的第4大原因。该应用程序的广泛的长期目标是了解儿童膀胱输尿管反流和反流性肾病的病理生理学，以最终提供最合适的治疗策略。为此，已经产生了小鼠系，其是膀胱输尿管反流的新型遗传模型。被命名为fgfr 2 Mes-/-（由于肾后肾间充质中成纤维细胞生长因子受体2的条件性缺失）的小鼠经常在输尿管芽诱导部位出现异常，这可能导致出生后幼龄小鼠中VUR的高发生率。许多患有持续性VUR（但无明显尿路感染）的成年fgfr 2 Mes-/-小鼠有瘢痕形成，与反流性肾病一致。这些相同的小鼠具有与转化生长因子β（TGF-2）介导的损伤一致的肌成纤维细胞转化的证据。我们的工作假设是，fgfr 2 Mes-/-小鼠代表了膀胱输尿管反流和无菌反流性肾病的独特遗传模型，并且TGF-2信号传导是介导反流性肾病中肾损伤的关键分子途径。为了检验这一假设，产生了以下目的：具体目的1：阐明fgfr 2 Mes-/-小鼠易于发生VUR的原因，检查输尿管、膀胱和输尿管-膀胱（输尿管囊泡）连接部的形成。具体目的2：完全表征fgfr 2 Mes-/-小鼠中VUR和反流性肾病的自然史。具体目标3：阐明异常TGF-2信号在反流性肾病进展中的作用，包括其作为治疗靶点的效用。这种独特的小鼠模型将允许仔细评估膀胱输尿管反流和反流性肾病的病理生理学，这将为患有这些疾病的儿童提供新的治疗策略。 公共卫生相关性： 膀胱输尿管反流（尿液从膀胱回流到输尿管并流向肾脏）是最常见的泌尿道出生缺陷。这通常会导致反流性肾病，这是儿童肾衰竭的主要原因。我们有一个突变的小鼠，发展反流和随后的反流性肾病。这种小鼠模型将帮助我们确定如何最好地治疗患有这种疾病的儿童。

DESCRIPTION (provided by applicant): Vesicoureteral reflux (VUR- backflow of urine from the bladder into the ureter) is the most common urogenital anomaly in children and reflux nephropathy is the 4th leading cause of chronic renal failure in children. The application's broad long-term objectives are to understand the pathophysiology of vesicoureteral reflux and reflux nephropathy in children to ultimately offer the most appropriate treatment strategies. To that end, a mouse line has been generated that is a novel genetic model of vesicoureteral reflux. The mice, designated fgfr2Mes-/- (due to conditional deletion of fibroblast growth factor receptor 2 from kidney metanephric mesenchyme), frequently have abnormalities in ureteric bud induction site(s), which likely leads to the high incidence of VUR in young post natal mice. Many adult fgfr2Mes-/- mice with persistent VUR (but no obvious urinary tract infections) have scarring, consistent with reflux nephropathy. These same mice have evidence of myofibroblast transformation consistent with transforming growth factor beta (TGF-2) mediated injury. It is our working hypothesis that the fgfr2Mes-/- mice represent a unique genetic model of vesicoureteral reflux and sterile reflux nephropathy, and that TGF-2 signaling is a key molecular pathway mediating renal injury in reflux nephropathy. To test this hypothesis, the following aims have been generated: Specific Aim 1: Elucidate why the fgfr2Mes-/- mice are prone to VUR, examining formation of the ureter, bladder and ureter-bladder (ureterovesicle) junction. Specific Aim 2: Completely characterize the natural history of VUR and reflux nephropathy in fgfr2Mes-/- mice. Specific Aim 3: Elucidate the role of aberrant TGF-2 signaling in the progression of reflux nephropathy, including its utility as a therapeutic target. This unique mouse model will permit careful evaluation of the pathophysiology of vesicoureteral reflux and reflux nephropathy, which should provide novel therapeutic strategies for children with these conditions. PUBLIC HEALTH RELEVANCE: Vesicoureteral reflux (backflow of urine from the bladder into the ureter toward the kidney) is the most common urinary tract birth defect. This often leads to reflux nephropathy, a leading cause of kidney failure in children. We have a mouse mutant that develops reflux and subsequent reflux nephropathy. This mouse model will help us determine how best to treat children with this condition.