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

描述（由申请人提供）：虽然患者会遇到各种先天性梗阻性尿路病，但这些疾病具有共同的病理终点：肾损伤和肾功能丧失。 梗阻性尿路病仍然是小儿肾功能不全和肾衰竭的主要原因，部分原因是即使在手术纠正尿路病变后，仍存在永久性肾损伤的可能性。最近，基础科学和临床研究都表明，肾脏能够在损伤后恢复肾脏结构和功能。然而，对肾脏的先天修复机制以及它们在慢性阻塞后如何受损知之甚少。重要的是，BMP-7蛋白是几个过程所必需的，这些过程有助于修复梗阻引起的肾损伤，包括阻断肾细胞的增殖。 TGF-β/纤维化对损伤的反应和肾结构的恢复。尽管如此， 由于BMP-7表达的HDAC依赖性抑制和随后的肾修复失调，长期阻塞后肾恢复的可能性降低。 考虑到BMP-7也是肾发生所需的，可能在产前期间阻塞的肾中BMP-7表达的丧失也具有显著的， 对肾脏成熟和肾脏的长期功能能力的不利影响尚不清楚。由于在梗阻性尿路病和其他导致慢性肾损伤的疾病患者中观察到BMP-7表达的缺失，因此必须更好地了解这一关键分子事件。因此，该项目涉及以下具体目标：（目的1）将通过使用用于同种型特异性HDAC抑制的药理学和基于siRNA的方法的组合来确定导致慢性阻塞后BMP-7转录抑制的分子机制，以评估个体HDAC蛋白在BMP-7转录调节中的作用。7的表达及其下游功能，有助于阻塞诱导的肾损伤的修复。 (AIM 2）将在成熟的肾脏中检查慢性阻塞后BMP-7表达丧失的长期影响。诱导型BMP-7敲除小鼠模型将用于模拟梗阻诱导的BMP-7表达丧失，并确定其对肾成熟和肾的长期功能能力的影响。(AIM 3）通过在先天性阻塞性尿路病的小鼠模型中检查其刺激肾脏的先天修复机制、确保适当的肾脏发育和保持肾功能的能力，来评估设计用于恢复阻塞性肾脏中BMP-7功能的方法的治疗潜力。总之，这些研究将导致更好地了解先天性修复机制的肾脏沿着新的，治疗方法，可用于优化再生潜力的发展中的肾脏在治疗先天性梗阻性尿路病。

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.