MECHANISMS DRIVING THE FORMATION OF POST-OPERATIVE PERITONEAL ADHESIONS

腹部手术后的伤口愈合过程会导致腹膜粘连的形成。 超过90%的接受这种手术的患者会发生这种情况。腹膜粘连是 含有大量肌成纤维细胞和血管平滑肌细胞(VSMCs)的纤维组织。 腹膜粘连可导致多种并发症，包括肠梗阻。肠梗阻 与严重的发病率有牵连，并造成死亡风险。外科干预可以用来 去除腹膜粘连，但这些患者有复发粘连性疾病的风险。因此， 迫切需要预防和/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。这些过程有 被认为是帮助纤维化疾病的一个重要功能。血小板衍生生长因子受体α 而β(PDGFRα和PDGFFRβ)参与了包括纤维化在内的多种疾病。PDGFRα通常表达为 在成纤维细胞中表达，而PDGFRβ在血管平滑肌细胞等壁细胞中表达。这些细胞中的PDGF信号转导 已被证明通过促进肌动蛋白组装来诱导机械转导通路。肌动蛋白组装可以 诱导肌钙蛋白相关转录因子和YAP1转录辅助因子的活性。 本研究的目的是探讨PDGF信号通路是否促进腹膜微循环的形成。 黏附通过激活肌动蛋白组装，从而诱导MRTF和YAP1的活性。我们会 通过使用新的体内方法来实现这一目标，例如PDGFR+阳性细胞的细胞消融技术 在老鼠身上。这些细胞类型也将使用NuTrap技术进行分子表征，该技术使我们能够识别 可能促进腹膜粘连形成的新途径。此外，我们还将调查 在这些相同类型的细胞中抑制机械转导通路的后果。最后，我们将验证我们的 从患者腹膜粘连组织分离的细胞中发现。 在这些研究结束时，我们将对驱动形成的分子机制有了新的见解。 腹膜粘连。具体地说，我们将了解PDGF信令和 血小板衍生生长因子受体α+和/或血小板衍生生长因子受体β+细胞的机械转导通路。这一知识可能使我们能够识别 预防或减少腹膜粘连和潜在其他形式的腹膜粘连形成的新方法 纤维化症。

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.