Phosphodiesterase 4 and Pulmonary Endothelial Barrier Function

肺微血管内皮细胞（PMVEC）在肺微血管之间形成连续的半渗透性屏障。 血流和间隙空间。铜绿假单胞菌，急性肺损伤的主要贡献者。 抑制一种外毒素ExoY，破坏PMVEC屏障并导致肺损伤。ExoY是可溶性的 在胞质溶胶中产生cAMP的腺苷酸环化酶。胞浆cAMP水平升高导致磷酸化 细胞质蛋白质如tau蛋白，微管网络的重组，内皮细胞的破坏 屏障和受损的O2/CO2交换。磷酸二酯酶（PDE）活性降低cAMP水平。 最近的证据表明，PDE 4 B中的特定突变是发展的主要风险因素。 急性肺损伤目前尚不清楚这种突变是否会导致PDE 4 B活性的增加或减少，或者 改变酶的亚细胞定位。也不清楚PDE 4 B活性的改变如何影响 导致急性肺损伤发生的风险增加。事实上，很少有研究 PDE 4 B活性如何有助于调节特定的cAMP介导的细胞功能。的 在本申请中概述的实验将阐明PDE 4 B在肺组织中的生理作用。 这将使我们更好地了解PDE 4 B突变如何导致微血管系统的增加。 发生急性肺损伤的风险。如果拟议研究的结果如预期， 证明了PDE 4 B的亚细胞定位是确定cAMP特异性的关键因素 信号通路这些结果也为急性肺损伤的治疗指明了新的途径 设计小分子和肽以重定向肺中PDE 4 B的亚细胞分布 内皮细胞 相关性（参见说明）： 急性肺损伤（ALI）是一种损害肺的内皮衬里，限制氧气输送到肺的疾病。 血最近的研究表明，一种特定的基因突变与糖尿病风险的显著增加有关。 发展中的ALI突变发生在一种叫做PDE 4 B的蛋白质中。我们的工作重点是了解 PDE 4 B的突变改变肺内皮功能并使个体易于发生ALI。

Pulmonary microvascular endothelial cells (PMVECs) form contiguous, semi-permeable barriers between the bloodstream and the interstitial space. Pseudomonas aeruginosa, a major contributor to acute lung injury. Injects an exotoxin, ExoY, that disrupts the PMVEC barrier and results in lung injury. ExoY is a soluble adenylyl cyclase that produces cAMP in the cytosol. Increased cytosolic cAMP levels lead to phosphorylation of cytosolic proteins such as tau, reorganization of the microtubule network, disruption of the endothelial barrier, and impaired O2/CO2 exchange. cAMP levels are lowered by phosphodiesterase (PDE) activity. Recent evidence suggests that a specific mutation in PDE4B is a major risk factor for the development of acute lung injury. It is not known whether this mutation causes an increase or decrease in PDE4B activity, or alters the subcellular localization of the enzyme. It is also not understood how alteration of PDE4B activity contributes to the increased risk for development of acute lung injury. In fact, few studies have examined how PDE4B activity contributes to the regulation of specific, cAMP-mediated cellular functions. The experiments outlined In this application will elucidate physiological roles of PDE4B in the pulmonary microvasculature and will give us a better understanding of how mutations in PDE4B lead to an increased risk of developing acute lung injury. If the results of the proposed studies are as anticipated then they will demonstrate that the subcellular localization of PDE4B is a critical factor in defining specificity in the cAMP signaling pathway. These results would also point to novel approaches for treatment of acute lung injury designing small molecules and peptides to redirect the subcellular distribution of PDE4B in pulmonary endothelium. RELEVANCE (See instructions): Acute lung injury (ALI) is a disease that damages the endothelial lining of the lung, limiting oxygen delivery to the blood. Recent studies have linked a specific genetic mutation with a siginificant increase in the risk of developing ALI. The mutation is In a protein called PDE4B. Our work focuses on understanding how mutations in PDE4B alter lung endothelial function and predispose individuals to develop ALI.