MECHANISMS DRIVING THE FORMATION OF POST-OPERATIVE PERITONEAL ADHESIONS

术后腹膜粘连形成的机制

• 批准号: 10620237
• 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/10620237
• 关键词: Ablation; Actins; Adhesions; Adhesives; Automobile Driving; Cell Separation; 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 接受此类手术的患者中 90% 以上都会发生腹膜粘连。 含有大量肌成纤维细胞和血管平滑肌细胞（VSMC）的纤维化组织。 腹膜粘连可导致多种并发症，包括肠梗阻。 已涉及严重的发病率并造成死亡风险，可采用手术干预措施。 去除腹膜粘连，但这些患者存在粘连疾病复发的风险。 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。 血小板衍生生长因子受体 α 被认为是帮助治疗纤维化疾病的重要功能。 PDGFRα 和 β（PDGFRα 和 PDGFRβ）与许多疾病有关，其中通常表达 PDGFRα。 PDGFRβ 在成纤维细胞中表达，而 PDGFRβ 在壁细胞中表达，例如这些细胞中的 VSMC 信号传导。 已被证明可以通过促进肌动蛋白组装来诱导机械传导途径。 诱导心肌素相关转录因子 (MRTF) 和 YAP1 转录辅助因子的活性。 该研究计划的目标是检查 PDGF 信号传导是否促进腹膜形成 我们将通过激活肌动蛋白组装从而诱导 MRTF 和 YAP1 的活性来实现粘连。 通过使用新颖的体内方法（例如 PDGFR+ 阳性细胞中的细胞消融技术）来实现这一目标 这些细胞类型也将使用 NuTrap 技术进行分子表征，使我们能够识别它们。 此外，我们将研究可能促进腹膜粘连形成的新途径。 最后，我们将验证我们的研究结果。 从患者腹膜粘连组织中分离出的细胞的发现。 在这些研究结束时，我们将对驱动形成的分子机制获得新的见解 具体来说，我们将了解 PDGF 信号传导与腹膜粘连之间是否存在相互作用。 这些知识可能使我们能够识别 PDGFRα+ 和/或 PDGFRβ+ 细胞中的机械传导途径。 预防或减少腹膜粘连和潜在其他形式粘连形成的新方法 纤维化。