THE ROLE OF BMP-7 IN THE PATHOGENESIS AND TREATMENT OF OBSTRUCTIVE UROPATHIES

描述(申请人提供)：虽然患者会遇到各种先天性梗阻性尿路疾病，但这些疾病有一个共同的病理终点：肾脏损伤和肾功能丧失。梗阻性尿路疾病仍然是儿童肾功能不全和肾功能衰竭的主要原因，部分原因是即使在手术矫正尿路病理后，永久性肾损伤的可能性仍然存在。近年来，基础科学和临床研究都表明，肾脏在损伤后具有恢复肾脏结构和功能的能力。然而，人们对肾脏的先天修复机制以及慢性梗阻后肾脏如何受损知之甚少。重要的是，BMP-7蛋白是促进梗阻所致肾损伤修复的几个过程所必需的，包括停止对损伤的转化生长因子-b/纤维化反应和恢复肾脏结构。尽管如此， 由于依赖HDAC抑制BMP-7的表达以及随后肾脏修复的失调，长时间梗阻后肾脏恢复的可能性降低。鉴于BMP-7也是肾脏发生所必需的，很可能BMP-7在围产期梗阻肾脏中的表达缺失也具有显著的意义， 对肾脏成熟和肾脏长期功能能力的不良影响尚不清楚。由于在梗阻性尿路疾病和其他导致慢性肾损伤的患者中观察到BMP-7的表达缺失，因此有必要对这一关键的分子事件有更好的了解。因此，本项目针对以下特定目标：(目标1)慢性梗阻后导致BMP-7转录抑制的分子机制将通过结合使用药理学和基于siRNA的异构体特异性HDAC抑制方法来确定，以评估单个HDAC蛋白在调节BMP-7表达中的作用及其有助于修复梗阻所致肾损伤的下游功能。(目的2)研究慢性梗阻后BMP-7表达缺失对成熟肾脏的长期影响。可诱导的BMP-7基因敲除小鼠模型将被用来模拟梗阻诱导的BMP-7表达的丢失，并确定其对肾脏成熟和肾脏长期功能能力的影响。(目的3)在先天性梗阻性尿路病小鼠模型中，旨在恢复梗阻肾脏BMP-7功能的方法的治疗潜力将通过检测它们刺激肾脏的固有修复机制、确保肾脏正常发育和保护肾功能的能力来评估。总之，这些研究将使人们更好地了解肾脏的先天修复机制，以及在先天性梗阻性尿路疾病的治疗过程中，可用于优化发育中的肾脏的再生潜力的新的治疗方法。 公共卫生相关性：先天性梗阻性尿路疾病是儿童慢性肾脏疾病和肾移植的主要原因。虽然目前的手术方法通常能够纠正这些发育异常，但在许多情况下，即使在尿路功能成功恢复后，永久性肾损伤的可能性仍然存在。这项研究旨在更好地了解慢性梗阻后肾脏的固有修复机制是如何受损的，长期目标是开发新的治疗方法，以优化肾脏的再生潜力，并在治疗梗阻性尿路疾病患者期间保护肾功能。

DESCRIPTION (provided by applicant): While a variety of congenital obstructive uropathies are encountered in patients, these conditions have a common pathological endpoint: renal injury and loss of kidney function. Obstructive uropathies remain the leading cause of pediatric renal insufficiency and renal failure, in part, because the potential fo permanent renal injury remains even following the surgical correction of pathologies of the urinary tract. Recently, both basic science and clinical studies have demonstrated that the kidney is capable of restoring renal structure and function following injury. However, little is known about the innate repair mechanisms of the kidney and how they become impaired following chronic obstruction. Importantly, the BMP-7 protein is required for several processes that contribute to the repair of obstruction-induced renal injuries, including the cessaion of the TGF-b/fibrotic response to injury and the restoration of renal architecture. Nonetheless, the potential for renal recovery following prolonged obstruction is diminished due to the HDAC-dependent suppression of BMP-7 expression and the subsequent dysregulation of kidney repair. Given that BMP-7 is also required for nephrogenesis, it is likely that the los of BMP-7 expression in the obstructed kidney during the prenatal period also has significant, adverse effects on renal maturation and the long-term functional capacity of the kidney that are not yet understood. Since the loss of BMP-7 expression has been observed in patients with obstructive uropathies and other conditions that lead to chronic renal injury, it is imperative to develop a better understanding of this pivotal molecular event. Thus, this projec addresses the following specific aims: (AIM 1) The molecular mechanisms that lead to the suppression of Bmp-7 transcription following chronic obstruction will be determined by using a combination of pharmacologic and siRNA-based approaches for isoform-specific HDAC inhibition to assess the role of individual HDAC proteins in the regulation of BMP-7 expression and its downstream functions that contribute to the repair of obstruction-induced renal injuries. (AIM 2) The long-term effects of the loss of BMP-7 expression following chronic obstruction will be examined in the maturing kidney. An inducible Bmp-7 knockout mouse model will be used to mimic the obstruction- induced loss of BMP-7 expression and to determine its effects on renal maturation and the long-term functional capacity of the kidney. (AIM 3) The therapeutic potential of approaches designed to restore BMP-7 function in the obstructed kidney will be evaluated by examining their ability to stimulate the innate repair mechanisms of the kidney, ensure proper renal development, and preserve kidney function in a mouse model of congenital obstructive uropathy. Together, these studies will lead to a better understanding of the innate repair mechanisms of the kidney along with novel, therapeutic approaches that may be used to optimize the regenerative potential of the developing kidney during the treatment of congenital obstructive uropathies. PUBLIC HEALTH RELEVANCE: Congenital obstructive uropathies are the leading cause of chronic kidney disease and kidney transplants in the pediatric population. While current surgical approaches are often able to correct these developmental abnormalities, the potential for permanent renal injury remains in many cases even after urinary tract function is successfully restored. This study aims to better understand how the innate repair mechanisms of the kidney become impaired following chronic obstruction with the long-term goal of developing novel, therapeutic approaches to optimize the regenerative potential of the kidney and preserve renal function during the treatment of patients with obstructive uropathies.