RICE POST-DOC/TECHNICIAN SUPPORT

该子项目是利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得主要资金， 因此可以在其他CRISP条目中表示。列出的机构是 中心，不一定是研究者的机构。 肌成纤维细胞是组织重建和修复所必需的细胞。事实上，在某些情况下，肌成纤维细胞持续存在并继续分泌细胞外基质，这使它们与肺间质纤维化有关。一些研究表明，一氧化氮（NO）介导的信号可能是重要的，在调节肌成纤维细胞表型。NO产生的抑制导致肌成纤维细胞积累增加; NO减少肌成纤维细胞积累和胶原沉积;转化生长因子（TGF），一种已知的肌成纤维细胞分化激活剂，阻断肌成纤维细胞凋亡。在体内，内皮型一氧化氮合酶（eNOS）基因敲除小鼠经历长期的肺纤维化的促纤维化剂博莱霉素的反应，表明eNOS在调节肌成纤维细胞增殖和/或凋亡。eNOS基因启动子可以被上皮细胞中层流的机械力诱导的事实，以及观察到其他基因，特别是平滑肌肌动蛋白（ASMA），在肌成纤维细胞中受到机械转录调节，表明了在肌成纤维细胞中调节eNOS表达并因此凋亡的潜在机制。因此，我们推测肌成纤维细胞的收缩通过eNOS信号介导其凋亡。在我们目前的建议中，我们正在研究三个具体的目标，以扩大我们对机械应力和NO在调节肌成纤维细胞中的作用的认识。第一，我们正在评估机械应力对肺肌成纤维细胞eNOS表达的作用;第二，我们正在确定NO对肺肌成纤维细胞凋亡的作用;第三，我们正在评估肌节肌球蛋白的缺失对博来霉素诱导的肺纤维化的影响。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Myofibroblasts are necessary cells for tissue remodeling and repair. The fact that, under certain circumstances, myofibroblasts persist and continue to secrete extracellular matrix has implicated them in interstitial fibrosis of the lung. Several studies suggest that nitric oxide (NO)-mediated signals may be important in regulating myofibroblast phenotypes. Inhibition of NO production leads to increased accumulation of myofibroblasts; NO reduces myofibroblast accumulation and collagen deposition; and transforming growth factor ¿ (TGF¿), a known activator of myofibroblast differentiation, blocks myofibroblast apoptosis. In vivo, endothelial NOS (eNOS) knockout mice experience prolonged pulmonary fibrosis in response to the profibrotic agent bleomycin, suggesting that eNOS operates in regulating myofibroblast proliferation and/or apoptosis. The fact that the eNOS gene promoter can be induced by the mechanical force of laminar flow in epithelial cells, and the observation that other genes, ¿ smooth muscle actin (ASMA) in particular, are mechanotranscriptionally regulated in myofibroblasts, suggests a potential mechanism for regulating the expression of eNOS and thus apoptosis, in myofibroblasts. Therefore, we hypothesize that contraction of myofibroblasts mediates their apoptosis via eNOS signaling. In our current proposal, we are investigating three specific aims to extend our knowledge of the role of mechanical stress and NO in regulating myofibroblasts. One, we are evaluating the role of mechanical stress on pulmonary myofibroblast eNOS expression; two, we are determining the role of NO on pulmonary myofibroblast apoptosis; and three, we are assessing the deletion of sarcomeric myosin on bleomycin induced pulmonary fibrosis in vivo.