Partial Bladder Outlet Obstruction: Mechanisms of Injury and Novel Repair Strategies

项目摘要/摘要 先天性和获得性泌尿系功能性和解剖性膀胱梗阻 异常导致膀胱容量减少，顺应性降低，尿路上皮功能障碍，以及 大小便失禁。肠膀胱成形术被用作增加膀胱容量和减少膀胱体积的主要策略 为保护梗阻性膀胱病患者的肾功能，应采取高膀胱内压治疗。 然而，自体胃肠道移植物中可吸收的肠上皮的存在经常导致 处理慢性尿路感染、粘液产生和代谢异常等并发症 一旦整合到尿路中。丝素(SF)生物材料提供了一种特殊的物理组合 特点：抗拉强度和弹性高，加工灵活性多样，可控 可降解性和低免疫原性制造用于治疗梗阻性膀胱的现成支架 疾病。双层(BL)SF支架结合抗膀胱术重建膀胱的新策略 纤维化治疗药物，卤代呋喃酮和ABT-263，将被研究其恢复正常尿动力学的能力。 参数并促进新开发的部分节段性脑缺血大动物模型的优越结构重构 膀胱出口梗阻(PBOO)。在机制上，我们将利用最先进的、集成的转录和 蛋白质组表达谱了解梗阻性膀胱损伤的严重程度如何控制关键 膀胱损伤反应的分子调节器产生不同的疾病表型。在这项提案中，我们 将挑战以下总体假设：无细胞BLSF基质与抗纤维化化合物相结合 将为慢性梗阻膀胱提供一种更好的恢复正常膀胱功能的方法 与小肠膀胱成形术进行比较。应用程序的具体目标是：具体目标1：确定如何 PBOO的严重程度影响膀胱损伤反应的分子调节。具体目标2：评估 慢性pBOO对去细胞膀胱成形术后膀胱再生过程的影响 BLSF移植。具体目标3：确定抗肝纤维化药物与补肾活血方联合应用的疗效 改善梗阻性膀胱功能障碍的支架。

PROJECT SUMMARY/ABSTRACT Functional and anatomical obstruction of the urinary bladder from congenital and acquired urologic abnormalities results in reduced bladder capacity, diminished compliance, urothelial dysfunction, and incontinence. Enterocystoplasty is utilized as the primary strategy to increase bladder capacity and decrease high intravesical pressures in order to preserve renal function in patients with obstructive bladder disease. However, the presence of absorptive intestinal epithelium in autologous gastrointestinal grafts frequently leads to serve complications such as chronic urinary tract infection, mucus production, and metabolic abnormalities once integrated into the urinary tract. Silk fibroin (SF) biomaterials provide an exceptional combination of physical characteristics including high tensile strength and elasticity, diverse processing flexibility, controllable degradability, and low immunogenicity to create “off-the-shelf” scaffolds for treatment of obstructive bladder disease. Novel bladder reconstructive strategies employing bi-layer (BL) SF scaffolds in combination with anti- fibrotic therapeutics, halofuginone and ABT-263, will be investigated for their ability to restore normal urodynamic parameters and promote superior constructive remodeling in a newly developed, large animal model of partial bladder outlet obstruction (pBOO). Mechanistically, we will utilize state-of-the-art, integrated transcriptomic and proteomic expression profiling to understand how the severity of obstructive bladder damage controls key molecular regulators of bladder injury responses to produce diverse disease phenotypes. In this proposal, we will challenge the overall hypothesis that: acellular BLSF matrices in combination with anti-fibrotic compounds will provide a superior approach for restoring normal bladder function in chronically obstructed bladders in comparison to enterocystoplasty. The specific aims of the application are: Specific Aim 1: Determine how the severity of pBOO influences molecular regulators of bladder injury responses. Specific Aim 2: Evaluate the impact of chronic pBOO on bladder regenerative processes following augmentation cystoplasty with acellular BLSF grafts. Specific Aim 3: Determine the efficacy of anti-fibrotic therapeutics in combination with BLSF scaffolds to ameliorate obstructed bladder dysfunction.