Targeting Macrophage to Improve the Outcomes of Urogynecologic Meshes in Diabetic Women

项目摘要 盆底疾病(PFD)，如压力性尿失禁(SUI)和/或盆腔器官脱垂(POP) 常见和昂贵的情况下，女性的终身手术修复的风险为20%。对于SUI的治疗， 放置由聚丙烯网片制成的尿路中间吊带是最广泛使用的手术。 对于POP，还使用聚丙烯网状物来改善高故障率(两年后高达40%；60% 7年后)的自然组织修复。遗憾的是，这些网格与网格相关 并发症，最常见的是网片通过阴道上皮外露和疼痛。这些并发症 糖尿病妇女的发病率更高，大约是普通人群的3倍。 然而，对糖尿病增加网状并发症风险的机制的研究一直是 斯坎特。据估计，在美国每年接受网状手术的35万名女性中，超过14%的人是 已知的糖尿病患者。由于接受SUI和POP手术的女性人数预计将增加 到2050年，将有更多的糖尿病女性接受网状治疗。因此，对机制的洞察具有 有可能显著影响医疗保健。 任何宿主对外来物质的典型反应，我们小组的研究表明巨噬细胞是 调节对网格的响应的关键单元格类型。然而，巨噬细胞的一个不可逆转的衰老过程 糖尿病患者的高血糖会加速衰老。这些过早衰老的人 巨噬细胞与吞噬功能缺陷和免疫反应调节有关 网状等异物。此外，我们还发现，巨噬细胞表型从亲本细胞转变为单核细胞。 从糖尿病妇女切除的网状组织标本中，炎性M1到促进愈合的M2受损 网状并发症。根据我们小组和其他人的发现，我们假设巨噬细胞 M1向M2转换受损的衰老相关功能障碍是导致高血压的主要机制 糖尿病妇女的网状并发症风险增加。为了验证我们的假设，我们提出了以下建议 在中年糖尿病大鼠模型中：目的1：确定糖尿病对宿主反应和 目的2：确定糖尿病对网状结构的影响。 巨噬细胞衰老的获得及巨噬细胞的HDAC3/IL-4信号通路 植入部位；目标3：通过替换功能失调的巨噬细胞来改善网状细胞与组织的结合 从健康大鼠分离单核细胞或通过选择性抑制HDAC3促进M1向M2转变 由新型病毒载体(AAV-CD68p-shHDAC3)介导。 本计划中的数据将提供以下创新交付成果：1)通过以下方式解决知识差距 确定糖尿病增加网状并发症风险的机制；2)开发新的 基于巨噬细胞的疗法在临床上是可翻译的，并可能适用于其他设备。

PROJECT ABSTRACT Pelvic floor disorders (PFDs) such as stress urinary incontinence (SUI) and/or pelvic organ prolapse (POP) are common and costly situation in women with a lifetime risk of surgical repair of 20%. For the treatment of SUI, placement of a mid-urethral sling manufactured from polypropylene mesh is the most widely used procedure. For POP, polypropylene meshes are also used to improve on the high failure rates (up to 40% at 2 years; 60% at 7 years) of native tissue repairs. Unfortunately, these meshes are associated with mesh related complications, most commonly exposure of mesh through vaginal epithelium and pain. These complications occur more frequently in diabetic women, roughly 3 times more in comparison to the general population. However, research into mechanisms by which diabetes increases the risks of mesh complications has been scant. It is estimated that among the 350,000 women who receive meshes annually in the US, over 14% are known diabetics. Since the number of women undergoing SUI and POP surgeries is predicted to increase by 50% by 2050, more diabetic women will receive meshes. Therefore, insight into the mechanisms has the potential to markedly impact health care. Typical of any host responses to a foreign material, studies from our group have shown that macrophage is the key cell type that mediates the responses to meshes. However, an irreversible aging process of macrophages (senescence) is accelerated by high level of blood glucose in diabetic patients. These premature senescent macrophages are associated with functional deficit in phagocytosis and regulation of immune response to foreign bodies such as mesh. In addition, we found that macrophage phenotypic transition from pro- inflammatory M1 to pro-healing M2 was impaired in mesh-tissue specimens excised from diabetic women with mesh complications. Based on the findings from our group and others, we hypothesized that macrophage senescence associated dysfunction with impaired M1 to M2 transition is the primary mechanism leading to the increased risk of mesh complications in diabetic women. We propose the following aims to test our hypothesis in a middle-aged diabetic rat model: Aim 1: To determine the impact of diabetes on the host response and mesh-tissue incorporation following mesh implantation; Aim 2: To determine the impact of diabetes on the acquisition of macrophage senescence and HDAC3/IL-4 signaling pathway in macrophages at the mesh implantation site; Aim 3: To improve mesh incorporation with tissue by replacing dysfunctional macrophages with monocytes isolated from healthy rats or promoting M1 to M2 transition via selective HDAC3 inhibition mediated by a novel viral vector (AAV-CD68p-shHDAC3). The data from this proposal will offer the following innovative deliverables: 1) address the knowledge gap by defining the mechanism by which diabetes increases the risk of mesh complications; 2) develop novel macrophage-based therapies that is clinically translatable with potential applicability to other devices.