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Regulation of endothelial permeability in sepsis

脓毒症中内皮通透性的调节

基本信息

批准号：
8525409
负责人：
MICHELLE L MATTER
金额：
$ 27.86万
依托单位：
UNIVERSITY OF HAWAII AT MANOA
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-01 至 2017-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8525409
关键词：
Adherens Junction Area Attenuated Blood Vessels Cells Cellular biology Cessation of life Clinical Complex Cytoskeletal Proteins Cytoskeleton Data Death Rate Defect Development Diffuse Disease Dominant-Negative Mutation Edema Electrical Resistance Endothelial Cells Endotoxins Event Extravasation Fibrosis Frequencies GTP-Binding Proteins Gene Transfer Goals Human Inflammation Inflammatory Response Intra-abdominal Knockout Mice Lead Ligation Liquid substance Measures Mechanical Stress Mechanics Mediating Medical Modeling Molecular Molecular Biology Techniques Multiple Organ Failure Mus Null Lymphocytes Pathogenesis Pathologic Patients Perforation Permeability Phosphorylation Physiological Pneumonia Publishing Pulsatile Flow Puncture procedure Regulation Reporting Role Sepsis Signal Pathway Signal Transduction Site Stretching System Testing Therapeutic Therapeutic Intervention Time Tissues Vascular Permeabilities Work beta catenin cadherin 5 clinically relevant cytokine filamin in vivo innovation insight monolayer mortality mouse model new therapeutic target novel novel therapeutic intervention pre-clinical prevent septic shear stress therapeutic target

项目摘要

DESCRIPTION (provided by applicant): Sepsis remains a current medical challenge. The frequency of this devastating disease is increasing and is associated with a death rate as high as 70%. It is often exacerbated by edema, which promotes fluid accumulation in tissues, causes an enhanced inflammatory response and induces fibrosis. Over time this can lead multiple organ failure and death. Currently there are no therapies for blocking vascular leakage in sepsis. This is primarily because the molecular mechanisms regulating vascular permeability are not completely understood. Focusing on the mechanisms of vascular permeability would potentially provide valuable targets for therapeutic intervention to prevent inflammation and edema due to sepsis. We have identified a novel mechanism by which vascular barrier integrity is maintained. The primary goal of this proposal is to elucidate this mechanism further and thereby identify potential new therapeutic targets. We have previously reported an interaction between RRas and Filamin A (FLN). RRas, an intracellular GTP-binding protein, is primarily expressed in endothelial cells in vivo and is a regulator of arterial endothelial function. The cytoskeletal protein FLN is required for cell-cell contact in vascular development. Indeed, FLN-null mice die of vascular defects. We have recently reported that in arterial endothelial cells endogenous RRas interacts with endogenous FLN. Furthermore, endothelial barrier function is dependent upon active RRas and an association between RRas and FLN. Thus, we propose the innovative hypothesis that the RRas and FLN complex is a primary driver in maintaining endothelial barrier function. This proposal will focus on the RRas and FLN complex as a point of integration between several select signaling pathways involved in regulating vascular permeability. This study will test whether this RRas is a therapeutic target in preclinical mouse models of sepsis. .!

描述（由申请人提供）：脓毒症仍然是当前的医学挑战。这种毁灭性疾病的发生频率正在增加，死亡率高达70%。它通常因水肿而加重，水肿会促进组织中液体积聚，引起炎症反应增强并诱发纤维化。随着时间的推移，这可能导致多器官衰竭和死亡。目前尚无治疗脓毒症血管渗漏的方法。这主要是因为调控血管通透性的分子机制尚不完全清楚。关注血管通透性的机制可能为预防脓毒症引起的炎症和水肿的治疗干预提供有价值的靶点。我们已经确定了一种维持血管屏障完整性的新机制。本提案的主要目标是进一步阐明这一机制，从而确定潜在的新治疗靶点。我们之前报道过RRas和Filamin A （FLN）之间的相互作用。RRas是一种细胞内gtp结合蛋白，在体内主要在内皮细胞中表达，是动脉内皮功能的调节剂。在血管发育过程中，细胞骨架蛋白FLN是细胞间接触所必需的。事实上，fln缺失小鼠死于血管缺陷。我们最近报道了在动脉内皮细胞中内源性RRas与内源性FLN相互作用。此外，内皮屏障功能依赖于活性RRas以及RRas与FLN之间的关联。因此，我们提出了一个创新的假设，即RRas和FLN复合物是维持内皮屏障功能的主要驱动因素。本研究将重点关注RRas和FLN复合物作为参与调节血管通透性的几种选择信号通路之间的整合点。这项研究将测试这些RRas是否在脓毒症的临床前小鼠模型中是一种治疗靶点。