MECHANISMS DRIVING THE FORMATION OF POST-OPERATIVE PERITONEAL ADHESIONS

腹内手术后的伤口愈合过程导致腹膜粘连的形成

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.