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

靶向巨噬细胞以改善糖尿病女性泌尿妇科网片的结果

• 批准号: 9809148
• 负责人: Rui Liang
• 金额: $ 21.56万
• 依托单位: MAGEE-WOMEN'S RES INST AND FOUNDATION
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-15 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9809148
• 关键词: Abnormal Macrophage; Address; Aging; Blood Glucose; Cell Aging; Complex; DNA cassette; Data; Dependovirus; Devices; Diabetes Mellitus; Epithelium; Failure; Foreign Bodies; Foreign-Body Reaction; Functional disorder; General Population; Genetic Transcription; Goals; HDAC3 gene; Healthcare; Histone Deacetylase; IL4 Signaling Pathway; Immune response; Immunofluorescence Immunologic; Impairment; Incidence; Inflammatory; Infusion procedures; Interleukin-4; Knowledge; Mediating; Messenger RNA; Operative Surgical Procedures; Outcome; Pain; Pathway interactions; Pelvic Floor Disorders; Phagocytosis; Phenotype; Polypropylenes; Prevention strategy; Procedures; Process; Rattus; Research; Risk; Signal Transduction; Site; Specimen; Stress Urinary Incontinence; Testing; Therapeutic; Time; Tissues; Up-Regulation; Urethra; Urinary Incontinence; Vagina; Viral Vector; Woman; base; capsule; cell type; clinically translatable; cost; cytokine; design; diabetic; diabetic patient; diabetic rat; epigenomics; experience; healing; immune phagocytosis; immunoregulation; implantable device; implantation; improved; improved outcome; innovation; insight; intraperitoneal; lifetime risk; macrophage; middle age; monocyte; nano-string; new product development; non-diabetic; non-healing wounds; novel; pelvic organ prolapse; premature; promoter; repaired; response; senescence; surgical risk; tissue repair

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.

项目摘要 骨盆底疾病（PFDs），例如压力性尿失禁（SUI）和/或骨盆器官脱垂（POP）， 常见和昂贵的情况下，妇女的一生风险的手术修复的20%。对于SUI的治疗， 放置由聚丙烯网制成的尿道中段悬带是最广泛使用的方法。 对于POP，聚丙烯补片也用于改善高失效率（2年时高达40%; 60%） 7岁时）的天然组织修复。不幸的是，这些网格与网格相关 并发症，最常见的是补片通过阴道上皮暴露和疼痛。这些并发症 糖尿病女性的发病率更高，大约是普通人群的3倍。 然而，对糖尿病增加补片并发症风险的机制的研究已经被证实。 少。据估计，在美国每年接受补片的35万名妇女中， 已知的糖尿病由于预计接受SUI和POP手术的女性数量将增加 到2050年，50%的糖尿病女性将接受补片。因此，深入了解这些机制， 可能会对医疗保健产生重大影响。 我们小组的研究表明，巨噬细胞是宿主对外来物质的典型反应， 介导对网格的响应的关键细胞类型。然而，巨噬细胞的不可逆衰老过程 在糖尿病患者中，高水平的血糖加速了衰老。这些过早衰老的 巨噬细胞与吞噬功能和免疫应答调节的功能缺陷有关， 异物，例如网状物。此外，我们发现巨噬细胞表型从亲- 从糖尿病女性切除的网状组织样本中，炎症M1到促愈合M2受损， 补片并发症。基于我们小组和其他人的发现，我们假设巨噬细胞 衰老相关的功能障碍与受损的M1到M2的转换是主要的机制， 糖尿病女性补片并发症风险增加。我们提出以下目标来检验我们的假设 目的1：确定糖尿病对宿主反应的影响， 补片植入后的补片-组织结合;目的2：确定糖尿病对 在网状物处巨噬细胞中获得巨噬细胞衰老和HDAC3/IL-4信号通路 植入部位;目的3：通过替换功能障碍的巨噬细胞来改善补片与组织的结合 与从健康大鼠分离的单核细胞或通过选择性HDAC3抑制促进M1向M2转变 通过新型病毒载体（AAV-CD68 p-shHDAC3）介导的方法， 本提案中的数据将提供以下创新成果：1）通过以下方式弥补知识差距 确定糖尿病增加补片并发症风险的机制; 2）开发新的 基于巨噬细胞的疗法，其在临床上可转化为其他器械的潜在适用性。