Phosphodiesterase 4 and Pulmonary Endothelial Barrier Function

肺微血管内皮细胞(PMVECs)形成连续的、半透明的屏障 血流和间质间隙。铜绿假单胞菌，急性肺损伤的主要贡献者。 注射外毒素ExoY，破坏PMVEC屏障，导致肺损伤。ExoY是一种可溶的 腺苷环化酶，在胞浆中产生cAMP。胞内cAMP水平升高导致磷酸化 胞浆蛋白，如tau，微管网络的重组，内皮细胞的破坏 屏障，O2/CO2交换受损。磷酸二酯酶(PDE)活性可降低cAMP水平。 最近的证据表明，PDE4B中的一个特定突变是发生糖尿病的主要危险因素 急性肺损伤。目前尚不清楚这种突变是导致PDE4B活性增加还是减少，或者 改变酶的亚细胞定位。也不知道PDE4B活性的改变是如何 导致发生急性肺损伤的风险增加。事实上，很少有研究考察过 PDE4B活性如何参与cAMP介导的特定细胞功能的调节。这个 本申请中概述的实验将阐明PDE4B在肺组织中的生理作用。 并将使我们更好地理解PDE4B基因突变是如何导致 发生急性肺损伤的风险。如果拟议研究的结果如预期，那么他们将 证明PDE4B的亚细胞定位是决定cAMP特异性的关键因素 信号通路。这些结果也将为急性肺损伤的治疗提供新的方法。 设计小分子和多肽来重定向PDE4B在肺组织中的亚细胞分布 内皮细胞。 相关性(请参阅说明)： 急性肺损伤(ALI)是一种损害肺内皮细胞衬里的疾病，将氧气输送限制在 鲜血。最近的研究表明，一种特定的基因突变与罹患癌症的风险显著增加有关。 发展阿里。这种突变存在于一种名为PDE4B的蛋白质中。我们的工作重点是了解 PDE4B基因突变改变肺内皮细胞功能，使个体易患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.