G-protein-induced Signaling of PMN-mediated Lung Injury

G 蛋白诱导的 PMN 介导的肺损伤信号转导

基本信息

批准号：
7316663
负责人：
ARSHAD RAHMAN
金额：
$ 30.48万
依托单位：
UNIVERSITY OF ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-04-01 至 2011-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7316663
关键词：
1-Phosphatidylinositol 3-Kinase Address Adhesions Adult Respiratory Distress Syndrome Air Binding Biochemical Blood Vessels Cell Adhesion Molecules Cell surface Cells Coagulation Process Complex Coupling Data Development Disease Edema Endothelial Cells Event Family Functional disorder Future G-Protein-Coupled Receptors G-substrate GTP-Binding Proteins Gene Expression Genetic Grant Host Defense ICAM1 gene Inflammatory Injury Integrins Intercellular adhesion molecule 1 Knowledge Leukocytes Light Liposomes Lung Mediating Mediator of activation protein Molecular Biology Molecular and Cellular Biology Mus PAR-1 Receptor Pathway interactions Phase Phosphatidylinositols Phosphoinositide-3-Kinase, Catalytic, Gamma Polypeptide Phosphotransferases Physiological Physiology Play Protein Isoforms Protein Kinase C Protein Overexpression Protein-Serine-Threonine Kinases Range Raptors Regulation Research Personnel Role Sepsis Serine Protease Signal Pathway Signal Transduction Sirolimus Small Interfering RNA Structure of parenchyma of lung Surface Testing Therapeutic Thrombin Tissues Vascular Endothelium base cell growth defense response in vivo interdisciplinary approach interest lung injury lung vascular injury migration mutant neutrophil novel programs receptor response trafficking upstream kinase

1-Phosphatidylinositol 3-Kinase Address Adhesions Adult Respiratory Distress Syndrome Air Binding Biochemical Blood Vessels Cell Adhesion Molecules Cell surface Cells Coagulation Process Complex Coupling Data Development Disease Edema Endothelial Cells Event Family Functional disorder Future G-Protein-Coupled Receptors G-substrate GTP-Binding Proteins Gene Expression Genetic Grant Host Defense ICAM1 gene Inflammatory Injury Integrins Intercellular adhesion molecule 1 Knowledge Leukocytes Light Liposomes Lung Mediating Mediator of activation protein Molecular Biology Molecular and Cellular Biology Mus PAR-1 Receptor Pathway interactions Phase Phosphatidylinositols Phosphoinositide-3-Kinase, Catalytic, Gamma Polypeptide Phosphotransferases Physiological Physiology Play Protein Isoforms Protein Kinase C Protein Overexpression Protein-Serine-Threonine Kinases Range Raptors Regulation Research Personnel Role Sepsis Serine Protease Signal Pathway Signal Transduction Sirolimus Small Interfering RNA Structure of parenchyma of lung Surface Testing Therapeutic Thrombin Tissues Vascular Endothelium base cell growth defense response in vivo interdisciplinary approach interest lung injury lung vascular injury migration mutant neutrophil novel programs receptor response trafficking upstream kinase

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项目摘要

DESCRIPTION (provided by applicant): The overall objective of the proposed studies in this renewal application is to define the mechanisms by which the procoagulant thrombin, a serine protease released during clotting initiated by sepsis or vascular injury, regulates the expression of adhesion molecule, ICAM-1, in endothelial cells, and thereby endothelial adhesivity toward neutrophil (PMN). In the last grant cycle, we showed that PKC(, PI3 kinase, and the downstream target Akt mediate thrombin-induced IKK/NF-(B activation and ICAM-1 expression in endothelial cells. We now have evidence that thrombin-induced IKK/NF-(B activation and ICAM-1 expression are tightly regulated through the functional coupling of PKC( and PI3 kinase to the mammalian target of rapamycin (mTOR). Our data show that mTOR down-regulates thrombin-induced ICAM-1 expression in endothelial cells by controlling a delayed and transient activation of NF-(B. In light of these findings, we hypothesize that thrombin activates mTOR complexes via PKC(- and PI3 kinase/Akt-dependent pathways and that activated mTOR complexes in turn down-regulate IKK/NF-(B activation and ICAM-1 expression in endothelial cells. We further postulate that loss of mTOR-mediated inhibition of thrombin- induced endothelial adhesivity leads to marked exacerbation in lung PMN sequestration and PMN-dependent lung vascular injury and tissue edema. We will address this hypothesis by completion of the following specific aims. Aim 1: Determine the role of mTOR complexes, mTOR-raptor and mTOR-rictor, in modulating thrombin-induced IKK/NF-(B activation, ICAM-1 expression, endothelial adhesivity, and PMN migration across endothelial barrier. Aim 2: Determine the role of PKC( in signaling thrombin-induced activation of mTOR complexes and in thereby modulating IKK/NF-(B activation, ICAM-1 expression, and PMN migration across endothelial barrier. Aim 3: Determine the role of PI3 kinase/Akt in mediating thrombin-induced activation of mTOR complexes, and in thereby modulating NF-(B activation, ICAM-1 expression, and PMN migration across endothelial barrier. Studies will utilize multidisciplinary approaches ranging from biochemical, cellular, and molecular biology to lung physiology to identify the critical inhibitory pathways that are integrated with the stimulatory pathways but in a temporally divergent fashion to tightly regulate ICAM-1 expression induced by thrombin. With the knowledge gained, we believe that it will be possible to block PMN-mediated lung vascular injury by promoting the specific inhibitory signaling events controlling ICAM-1 expression associated with intravascular coagulation. These studies may provide future directions for development of therapeutic strategies for inflammatory disease states such as Acute Respiratory Distress Syndrome (ARDS).

DESCRIPTION (provided by applicant): The overall objective of the proposed studies in this renewal application is to define the mechanisms by which the procoagulant thrombin, a serine protease released during clotting initiated by sepsis or vascular injury, regulates the expression of adhesion molecule, ICAM-1, in endothelial cells, and thereby endothelial adhesivity toward neutrophil (PMN).在上一个赠款周期中，我们表明PKC（，PI3激酶和下游靶标A介导凝血酶诱导的IKK/NF-（B激活和ICAM-1在内皮细胞中的表达。我们现在有证据表明，凝血酶诱导的IKK/NF-激活和ICAM-1的表达是通过函数COUNS的COU（B激活和ICAM-1表达）的pik（pi）（PI）（PI）（PI）（PI）（PI）（PI）（PI）（PI）（PIK（PI）（PIK）（PI）（PIK）（PIK）（PIK）（PIK）（PIK）（PIK kin）pik（雷帕霉素的哺乳动物靶标（MTOR）。我们的数据表明，MTOR通过控制NF-的延迟和瞬时激活凝血酶诱导的ICAM-1表达（b。鉴于这些发现向下调节IKK/NF-（内皮细胞中的B激活和ICAM-1表达。我们进一步假设MTOR介导的抑制凝血酶诱导的内皮粘附性的损失导致肺下粒和依赖PMN依赖PMN的肺血管造成肺血管造成的肺部PMN和PMN依赖于PMN的肺血管造成的肺血管造成和组织EDEMA显着加重。我们将通过完成以下特定目标来解决这一假设。 Aim 1: Determine the role of mTOR complexes, mTOR-raptor and mTOR-rictor, in modulating thrombin-induced IKK/NF-(B activation, ICAM-1 expression, endothelial adhesivity, and PMN migration across endothelial barrier. Aim 2: Determine the role of PKC( in signaling thrombin-induced activation of mTOR complexes and in thereby modulating IKK/NF-（B激活，ICAM-1表达和PMN跨内皮屏障迁移。目标3：确定PI3激酶/AKT在介导凝血酶诱导的MTOR复合物激活中的作用生化，细胞和分子生物学对肺部生理学，以识别与刺激途径相结合的关键抑制途径，但以时间分歧的方式与链霉素诱导的ICAM-1表达紧密地调节，我们可以通过促进PMN介导的肺血管造成的特异性损伤来诱导的ICAM-1表达。凝血。这些研究可能为开发炎症性疾病状态（例如急性呼吸窘迫综合征（ARDS））的治疗策略的发展提供了未来的方向。