MECHANISMS DRIVING THE FORMATION OF POST-OPERATIVE PERITONEAL ADHESIONS

术后腹膜粘连形成的机制

• 批准号: 10451679
• 负责人: William L Berry
• 金额: $ 36.25万
• 依托单位: UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10451679
• 关键词: Ablation; Actins; Adhesions; Adhesives; Automobile Driving; Cells; Disease; Extracellular Matrix; Fibrosis; Genetic Transcription; Goals; Intestinal Obstruction; Intra-abdominal; Knowledge; Lead; Learning; Molecular; Morbidity - disease rate; Mus; Myofibroblast; Operative Surgical Procedures; PDGFRB gene; Pathway interactions; Patients; Peritoneal; Platelet-Derived Growth Factor; Platelet-Derived Growth Factor alpha Receptor; Postoperative Period; Prevention therapy; Procedures; Process; Recurrence; Research; Risk; Signal Transduction; Smooth Muscle Myocytes; Techniques; Technology; Tissues; Vascular Smooth Muscle; cell type; cofactor; in vivo; insight; mechanotransduction; mortality risk; myocardin; novel; novel strategies; novel therapeutics; prevent; programs; therapeutic target; transcription factor; wound healing

The wound healing process that follows intra-abdominal surgery results in the formation of peritoneal adhesions which occurs in over 90% percent of patients who undergo this type of procedure. Peritoneal adhesions are fibrotic tissue that contains significant numbers of myofibroblasts and vascular smooth muscle cells (VSMCs). Peritoneal adhesions can lead to a multitude of complications, including bowel obstructions. Bowel obstructions have been implicated in severe morbidity and create a risk of mortality. Surgical interventions can be used to remove peritoneal adhesions, but there is a risk of recurrence of adhesive disease in these patients. Therefore, new therapies for the prevention and/or reversal of peritoneal adhesions are urgently needed. Myofibroblasts and VSMCs have the capacity to secrete and remodel extracellular matrix. These processes have been implicated as an important function to aid in fibrotic diseases. Platelet derived growth factor receptors α and β (PDGFRα and PDGFRβ) are involved in many diseases including fibrosis. PDGFRα is typically expressed in fibroblastic cells, whereas PDGFRβ is expressed in mural cells such as VSMCs. PDGF signaling in these cells has been shown to induce mechanotransduction pathways by promoting actin assembly. Actin assembly can induce the activity of Myocardin-Related Transcriptions Factors (MRTFs) and the YAP1 transcriptional cofactor. The goal of this research program is to examine whether PDGF signaling promotes the formation of peritoneal adhesions by activating actin assembly and thereby inducing the activity of MRTFs and YAP1. We will accomplish this goal by using novel in vivo approaches such as cell ablation techniques in PDGFR+ positive cells in mice. These cell types will also be molecularly characterized using NuTrap technology that allows us to identify novel pathways that may promote the formation of peritoneal adhesions. Moreover, we will investigate the consequences of inhibiting mechanotransduction pathways in these same cell types. Lastly, we will validate our findings in cells isolated from patients’ peritoneal adhesion tissue. At the end of these studies, we will have gained new insights into molecular mechanisms that drive the formation of peritoneal adhesions. Specifically, we will learn whether the interplay between PDGF signaling and the mechanotransduction pathways in PDGFRα+ and/or PDGFRβ+ cells. This knowledge may enable us to identify novel approaches to prevent or reduce the formation of peritoneal adhesions and potentially other forms of fibrosis.

腹腔内手术后的伤口愈合过程导致腹膜粘连的形成 这发生在超过90%的接受这种手术的患者中。腹膜粘连是 纤维化组织包含大量的肌成纤维细胞和血管平滑肌细胞（VSMC）。 腹膜粘连可导致多种并发症，包括肠梗阻。肠梗阻 与严重的发病率有关，并造成死亡风险。手术干预可用于 清除腹膜粘连，但这些患者存在粘连性疾病复发的风险。因此，我们认为， 迫切需要用于预防和/或逆转腹膜粘连的新疗法。 肌成纤维细胞和血管平滑肌细胞具有分泌和重塑细胞外基质的能力。这些进程 被认为是帮助纤维化疾病的重要功能。血小板衍生生长因子受体α 和β（PDGFRα和PDGFRβ）参与包括纤维化在内的许多疾病。PDGFRα通常表达于 在成纤维细胞中表达，而PDGFRβ在壁细胞如VSMC中表达。这些细胞中的PDGF信号传导 已经显示通过促进肌动蛋白组装来诱导机械转导途径。肌动蛋白组装可以 诱导心肌素相关转录因子（MRTF）和YAP 1转录辅因子的活性。 这项研究的目的是检查PDGF信号是否促进腹膜炎的形成。 通过激活肌动蛋白组装并由此诱导MRTF和YAP 1的活性来促进粘附。我们将 通过在PDGFR+阳性细胞中使用新的体内方法如细胞消融技术来实现这一目标 对小鼠这些细胞类型也将使用NuTrap技术进行分子表征，使我们能够识别 可能促进腹膜粘连形成的新途径。此外，我们将调查 在这些相同的细胞类型中抑制机械转导途径的后果。最后，我们将验证 从患者腹膜粘连组织中分离的细胞中发现。 在这些研究的最后，我们将获得新的见解，推动形成的分子机制， 腹膜粘连具体地说，我们将了解PDGF信号传导和细胞凋亡之间的相互作用是否与细胞凋亡有关。 PDGFRα+和/或PDGFRβ+细胞中的机械转导途径。这些知识可以帮助我们识别 预防或减少腹膜粘连和潜在的其它形式的腹膜粘连的形成的新方法 纤维化