Novel therapies for VALI-induced edema

VALI 引起的水肿的新疗法

• 批准号: 7548528
• 负责人: Joe G. N. Garcia
• 金额: $ 47.63万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7548528
• 关键词: Acute Lung Injury; Affect; Angiogenic Factor; Animal Model; Backcrossings; Biochemical; Blood Platelets; Blood Vessels; Calmodulin; Canis familiaris; Chromosome Mapping; Data; Disease; Dose; Edema; Endothelial Cells; Endothelium; Environmental air flow; Enzymes; Future; Genetic; Genome; In Vitro; Inflammatory Response; Laboratories; Link; Lipids; Lung; MYLK gene; Malnutrition; Mechanical ventilation; Mediating; Menotropins; Modeling; Molecular; Molecular Target; Movement; Mus; Myosin Light Chain Kinase; Organ failure; Oxidoreductase; Pathway interactions; Patients; Physiological; Pneumonia; Predisposition; Pulmonary Edema; Regulation; Reporting; Rho-associated kinase; Risk; Signal Transduction; Simvastatin; Testing; Thrombin; Vascular Permeabilities; Vascular remodeling; Ventilator; authority; day; hydroxymethylglutarate; in vivo; inhibitor/antagonist; lung injury; novel; novel therapeutics; response; rho GTP-Binding Proteins; skills; sphingosine 1-phosphate; therapeutic target

Sustained increases in vascular permeability, a defining feature ventilator-associated lung injury and multi-organ failure, prolongs the duration of physiologic derangement and the requirement for mechanical ventilation. Increased ventilator days enhance the risk of malnutrition and nosocomial/ventilator-associated pneumonia. Clearly there is a desperate need for new strategies to reduce vascular leak in patients receiving ventilation. Project 4 will utilize well-established models of murine and canine VALI to identify novel molecular targets and validate recently described molecular targets involved in VALI- induced edema formation. Importantly, we will test novel anti-edema strategies which target the endothelial cell cytoskeletal, a direct result of in vitro physiologic, biophysical, biochemical and molecular studies conducted by the Project Leader. SA #1 will test the effect of molecular strategies to reduce the activity of the Ca+2/calmodulin-dependent myosin light chain kinase in lung endothelium (EC MLCK), a critical cytoskeletal regulatory enzyme first cloned by the Garcia laboratory. EC MLCK is intimately involved in multiple aspects of the inflammatory response and directly participates in EC barrier regulation. SA #2 will examine the efficacy of sphingosine 1-phosphate (Sph 1-P), angiogenic factor critical to platelet-mediated vascular integrity, as novel therapy in animal models of ALl. We demonstrated that Sph 1-P produces rapid, sustained, and dose-dependent increases in the barrier integrity of in vitro and in vivo. SA #3 will utilize the lipid-lowering HMG Co A reductase inhibitor, simvastatin, to reduce VALI-induced edema formation. Recent reports including our own data, which indicate that the statins directly affect vascular remodeling, likely via the modulation of intracellular signaling mediated by Rho GTPases and Rho kinase, a pathway utilized by edemagenic agents (such as thrombin and VALI) to increase vascular leak. Finally, the identification of novel therapeutic targets for future barrier- protective strategies is essential for progress to be made in this devastating disorder. SA #4 will define murine strain differences in response to VALI-mediated vascular leak and utilize experimental progeny backcross strategies with genetic mapping of the murine genome to identify QTLs linked to susceptibility to VALI. The Project Leader, an authority on molecular mechanisms of vascular barrier regulation, combines exceptional complementary skills and experts in animal models of lung injury and mouse genetics. Given the profound physiologic derangements which accompany the vascular leak seen in VALI, we speculate that this project which will explore novel therapies and targets for VALI-induced pulmonary edema, will more quickly allow us to bridge the movement of scientific discovery into direct benefit for patients with Acute Lung Injury.

血管通透性的持续增加是呼吸机相关肺损伤和多器官衰竭的一个定义特征，延长了生理紊乱的持续时间和机械通气的要求。呼吸机使用天数的增加增加了营养不良和院内/呼吸机相关性肺炎的风险。显然，迫切需要新的策略来减少接受通气的患者的血管渗漏。项目4将利用完善的鼠和犬VALI模型来鉴定新的分子靶标，并验证最近描述的涉及VALI诱导水肿形成的分子靶标。重要的是，我们将测试靶向内皮细胞细胞骨架的新型抗水肿策略，这是项目负责人进行的体外生理、生物物理、生物化学和分子研究的直接结果。SA #1将测试降低肺内皮细胞中Ca+2/钙调蛋白依赖性肌球蛋白轻链激酶（EC MLCK）活性的分子策略的效果，EC MLCK是Garcia实验室首次克隆的关键细胞骨架调节酶。EC MLCK密切参与炎症反应的多个方面，并直接参与EC屏障调节。SA #2将检查1-磷酸鞘氨醇（Sph 1-P）（对血小板介导的血管完整性至关重要的血管生成因子）作为AL 1动物模型中的新疗法的功效。我们证明，Sph 1-P在体外和体内的屏障完整性产生快速，持续和剂量依赖性的增加。SA #3将利用降脂HMG CoA还原酶抑制剂辛伐他汀来减少VALI诱导的水肿形成。最近 包括我们自己的数据在内的报告表明，他汀类药物可能通过调节Rho GTP酶和Rho激酶介导的细胞内信号传导直接影响血管重塑，Rho GTP酶和Rho激酶是一种由水肿剂（如凝血酶和VALI）用于增加血管渗漏的途径。最后，为未来屏障保护策略确定新的治疗靶点对于在这种破坏性疾病中取得进展至关重要。SA #4将定义响应VALI介导的血管渗漏的鼠品系差异，并利用实验后代回交策略和鼠基因组的遗传作图来鉴定 与VALI易感性连锁的QTL。项目负责人是血管屏障调节分子机制的权威，结合了肺损伤和小鼠遗传学动物模型方面的特殊互补技能和专家。鉴于VALI中所见的血管渗漏伴随着严重的生理紊乱，我们推测，该项目将探索VALI诱导的肺水肿的新疗法和靶点，将使我们能够更快地将科学发现的运动与急性肺损伤患者的直接受益联系起来。