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（PFD），例如压力尿失禁（SUI）和/或骨盆器官脱垂（POP）是 终生维修风险20％的女性的常见且昂贵的情况。为了治疗Sui， 用聚丙烯网格制造的尿道中吊带的放置是最广泛使用的过程。 对于POP，聚丙烯网格也用于提高高衰竭率（2年时高达40％； 60％ 在7年）的天然组织维修。不幸的是，这些网格与网格相关 并发症，最常见的是通过阴道上皮和疼痛暴露于网格。这些并发症 糖尿病女性更频繁地发生，与一般人群相比，大约三倍。 但是，研究糖尿病增加网状并发症风险的机制的研究是 很少。据估计，在美国每年接收网格的35万妇女中，超过14％ 已知的糖尿病患者。由于预计接受SUI和流行手术的妇女人数将增加 到2050年，有50％的糖尿病女性将获得网眼。因此，对机制的见解具有 有可能影响医疗保健的潜力。 我们小组的研究表明，巨噬细胞的典型宿主反应是对异物的反应 介导对网格的响应的钥匙单元类型。但是，巨噬细胞不可逆转的老化过程 （衰老）在糖尿病患者的高血糖中加速了（衰老）。这些过早的衰老 巨噬细胞与吞噬作用的功能不足以及对免疫反应的调节有关 异物，例如网状。此外，我们发现巨噬细胞表型从促进 从糖尿病妇女切除的网格组织标本中，炎症M1至亲治疗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 衰老与M1受损与M2转变相关的功能障碍是导致的主要机制 糖尿病女性网状并发症的风险增加。我们提出以下旨在检验我们的假设的旨在 在中年糖尿病大鼠模型中：目标1：确定糖尿病对宿主反应的影响和 网格植入后的网格组织掺入；目标2：确定糖尿病对 巨噬细胞衰老和HDAC3/IL-4信号通路的获取 植入地点；目标3：通过更换功能失调的巨噬细胞来改善与组织合并 通过从健康大鼠中分离出的单核细胞或通过选择性HDAC3抑制促进M1到M2过渡 由新型病毒载体（AAV-CD68P-SHHHDAC3）介导。 该提案的数据将提供以下创新可交付成果：1）解决知识差距 定义糖尿病增加网状并发症风险的机制； 2）发展小说 基于巨噬细胞的疗法可在临床上转换，并可能适用于其他设备。