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

激活转录因子 6 (ATF6) 对内皮屏障功能障碍的保护作用。

• 批准号: 10399869
• 负责人: Konstantin G Kousoulas
• 金额: $ 14.81万
• 依托单位: LOUISIANA STATE UNIV A&M COL BATON ROUGE
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-25 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10399869
• 关键词: ATF6 gene; Acute Lung Injury; Adult Respiratory Distress Syndrome; Affect; Apoptosis; Applications Grants; Biogenesis; Biology; Blood; Blood Vessels; COVID-19; Cattle; Cells; Data; Development; Diabetes Mellitus; Disease; Disease Management; Electrolytes; Endoplasmic Reticulum; Endothelial Cells; Endothelium; Endotoxins; Enzymes; Exposure to; Functional disorder; Generations; Genes; HSP 90 inhibition; Health; Heat-Shock Proteins 90; Homeostasis; Hormone Antagonists; Human; Immunology; In Vitro; Inflammation; Inositol; Integral Membrane Protein; Investigation; Knockout Mice; Knowledge; Life; Lipopolysaccharides; Liquid substance; Lung; Lung diseases; Mediating; Molecular; Molecular Chaperones; Mus; Outcome; Pancreas; Pathogenesis; Pathologic; Pathology; Pathway interactions; Phosphotransferases; Productivity; Proteins; Publishing; Pulmonary Edema; Pulmonary Pathology; Pulmonary artery structure; Regulation; Respiratory distress; Role; Sepsis; Somatotropin-Releasing Hormone; Stress; Testing; Therapeutic; Time; base; endoplasmic reticulum stress; human tissue; in vivo; in vivo Model; inflammatory lung disease; inhibitor/antagonist; kifunensine; mouse model; novel therapeutic intervention; novel therapeutics; polypeptide; protein folding; repaired; response; sensor; therapeutic development

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

项目摘要 内皮屏障调节血管内液体、电解质和蛋白质的交换。 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)是重症 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。针对这些毁灭性疾病的新治疗策略的发展是 最迫切的需要。我们努力揭示EBD相关疾病的新治疗途径 Hsp90抑制剂和GHRH拮抗剂保护内皮屏障功能障碍，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 以及修复人体组织中的细胞反应，包括肺部。它由三个内质网跨膜组成 蛋白质：Ire 1α(肌醇需要酶1α)、PERK(胰腺内质网激酶)和ATF6 (激活转录因子6)。热休克蛋白90抑制或生长激素诱导UPR 释放激素拮抗剂拮抗Kifunensine(UPR抑制物)诱导的内皮细胞 体外高渗透性。我们的建议将重点放在ATF6在肺内皮屏障功能中的作用。 特定目标1将ATF6激活与内皮屏障功能联系起来，以证明支持 ATF6体外抗EBD作用的研究具体目标2将重点放在内毒素诱导的ALI的体内模型上，以 证实我们的体外研究结果。为此，我们将生成ATF6缺失的ATF6内皮特异性敲除 老鼠。我们的研究结果将丰富我们目前对内皮屏障调节的理解，以 为EBD相关疾病的管理提供新的目标。 1