Protective role of Activating Transcription Factor 6 (ATF6) against endothelial barrier dysfunction.

项目摘要 内皮屏障调节血液、电解质和蛋白质在血管中的交换。 墙，它受到动态重塑。这种屏障的功能受到各种条件的影响， 包括炎症、糖尿病和败血症。内皮屏障功能障碍（EBD）是严重的 呼吸系统疾病，如急性肺损伤（ALI）、急性呼吸窘迫综合征（ARDS）和 败血症针对这些破坏性病理的新治疗策略的开发是 最大的需要。我们努力揭示EBD相关疾病的新治疗途径， Hsp90抑制剂和GHRH拮抗剂可防止内皮屏障功能障碍，并诱导 未折叠蛋白反应（UPR）。这是一种高度保守的分子机制，能够启动保护性的 以及修复人体组织中的细胞反应，包括肺部。它由三个ER跨膜结构组成， 蛋白质：IRE1α（肌醇需要酶1α）、PERK（胰腺内质网激酶）和ATF 6 （激活转录因子6）。由于热休克蛋白90抑制或生长激素引起的UPR诱导 释放激素拮抗剂抵消Kifunensine（UPR抑制剂）诱导的内皮细胞 体外高渗透性。我们的建议将集中在ATF6在肺内皮屏障功能的影响。 特异性目的1将ATF6活化与内皮屏障功能相关联，以证明支持性的 ATF6在体外抗EBD的作用。具体目标2将集中于LPS诱导的ALI的体内模型， 证实了我们在体外的发现为此，我们将产生ATF6无效ATF6内皮特异性敲除， 小鼠我们的研究结果将丰富我们目前对内皮屏障调节的理解， 为EBD相关疾病的管理提供新的靶点。 1

Project Summary The endothelium barrier regulates the exchange of blood fluid, electrolytes and proteins across the vascular wall, and it is subjected to dynamic remodeling. The function of this barrier is affected by various conditions, including inflammation, diabetes and sepsis. Endothelial barrier dysfunction (EBD) is the hallmark of severe respiratory disease, such as Acute Lung Injury (ALI), Acute Respiratory Distress Syndrome (ARDS) and sepsis. The development of novel therapeutic strategies against these devastating pathologies is of the utmost need. Our endeavors to expose new therapeutic avenues towards EBD-related diseases revealed that Hsp90 inhibitors and GHRH antagonists protect against endothelial barrier dysfunction, and induce the Unfolded Protein Response (UPR). This is a highly conserved molecular machinery, able to initiate protective and repairing cellular responses in human tissues, including the lungs. It consists of three ER transmembrane proteins: IRE1α (inositol-requiring enzyme 1α), PERK (pancreatic endoplasmic reticulum kinase), and ATF6 (activating transcription factor 6). UPR induction due to heat shock protein 90 inhibition or growth hormone releasing hormone antagonists counteracted the Kifunensine (UPR suppressor) – induced endothelial hyperpermeability in vitro. Our proposal will focus on the effects of ATF6 in lung endothelial barrier function. Specific Aim 1 will associate ATF6 activation with endothelial barrier function, to demonstrate the supportive role of ATF6 against EBD in vitro. Specific Aim 2 will focus on an in vivo model of LPS-induced ALI, to substantiate our in vitro findings. To do so, we will generate ATF6 null ATF6 endothelial specific knock out mice. The outcomes of our study will enrich our current understanding on endothelial barrier regulation, to provide new targets for the management of diseases related to EBD. 1