RICE POST-DOC/TECHNICIAN SUPPORT

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 肌成纤维细胞是组织重塑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，这一事实表明它们与肺间质纤维化有关。一些研究表明，一氧化氮(NO)介导的信号可能在调控肌成纤维细胞表型中起重要作用。抑制NO的产生导致肌成纤维细胞的积聚增加；NO减少肌成纤维细胞的积聚和胶原沉积；转化生长因子(转化生长因子)，一种已知的肌成纤维细胞分化的激活剂，阻止肌成纤维细胞的凋亡。在体内，内皮型一氧化氮合酶(ENOS)基因敲除的小鼠在促纤维化药物博莱霉素的作用下出现了长时间的肺纤维化，这表明eNOS在调节肌成纤维细胞的增殖和/或凋亡方面起作用。ENOS基因启动子可以由上皮细胞层流的机械力诱导，而其他基因，特别是肌成纤维细胞中的平滑肌肌动蛋白(ASMA)是机械转录调控的，这提示了一种潜在的机制来调节eNOS的表达，从而在肌成纤维细胞中诱导细胞凋亡。因此，我们假设肌成纤维细胞的收缩通过eNOS信号转导其凋亡。在我们目前的提案中，我们正在研究三个具体的目标，以扩大我们对机械应激和NO在调控肌成纤维细胞中的作用的了解。第一，我们正在评估机械应激对肺肌成纤维细胞eNOS表达的影响；第二，我们正在确定NO在肺肌成纤维细胞凋亡中的作用；第三，我们正在评估肌球蛋白的缺失对博莱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.