Membrane Phospholipids: The Key Regulators of Tissue Factor Encryption/Decryption
Membrane Phospholipids: The Key Regulators of Tissue Factor Encryption/Decryption
批准号:
10401806
负责人:
Vijaya Mohan Rao Lella
金额:
$45.7万
依托单位国家:
美国
项目类别:
财政年份:
2015
资助国家:
美国
项目状态:
已结题
起止时间:
2015-09-01 至 2024-04-30
关键词:
AcuteAcute myocardial infarctionAddressAntigensAtherosclerosisBiologyBloodBlood CellsBlood Coagulation DisordersBlood Coagulation FactorBlood Coagulation Factor VIIBlood coagulationCell membraneCell surfaceCellsCoagulantsCoagulation ProcessComplexDataDevelopmentDiabetes MellitusDiseaseDown-RegulationEndothelial CellsEnsureEnzyme Inhibitor DrugsEnzymesEpithelial CellsEquilibriumEventFactor IXFactor VIIaFactor XGenerationsGlycoproteinsHealthHemorrhageHemostatic AgentsHemostatic functionHydrolysisInfectionInflammationInflammatoryInterphase CellInterventionIschemic StrokeKineticsKnockout MiceKnowledgeLeadLipoxygenaseMaintenanceMalignant NeoplasmsMediatingMembraneMembrane MicrodomainsMetabolismMolecular ConformationMorbidity - disease rateMusPathogenesisPathway interactionsPericytesPharmacologyPhospholipidsPlasmaPlayPreventiveProcessProteinsPublishingRegulationResearchRoleSepsisSphingomyelinaseSphingomyelinsStimulusTestingThromboplastinThrombosisThrombusTransgenic MiceUnstable anginaVascular Endothelial CellWild Type Mouseacid sphingomyelinaseatherogenesiscell injurycell typecofactorcohesionencryptionexperimental studyin vivoinhibitorinsightmacrophagemicrovesiclesmonocytemortalitymouse modelnovelnovel therapeuticsoverexpressionpreventresponsesphingomyelin synthasesystemic inflammatory responsethrombotictranscription factorvascular injury
中文摘要
在血管损伤时,血浆凝血因子VII(FVII)和激活的FVII(FVIIa)一起进入
与辅因子组织因子(Tf)接触,Tf在管壁内的细胞中组成性表达。
FVIIa与Tf形成络合物使FVIIa和Tf的催化活性显著增强
触发转铁蛋白介导的血液凝固。某些疾病条件可诱导循环血中转铁蛋白的表达
细胞和血管内皮细胞,从而允许循环血液和转铁蛋白之间直接接触,从而导致
血栓形成。虽然转铁蛋白介导的血液凝固是维持止血的关键,但异常的
激活组织因子介导的凝血系统导致血栓形成,这是急性心肌梗死的诱发事件
脑梗塞、缺血性中风和败血症。因此,对TF表达和活性的适当调节是
这不仅对维持止血平衡至关重要,而且对一般人的健康也至关重要。通常,大多数
在细胞中表达的Tf保持加密,几乎没有促凝活性,足以实现
止血,但不会引起血管内凝血。细胞损伤增强组织因子促凝血活性
大大不改变转铁蛋白抗原水平,即将隐匿性转铁蛋白转化为血栓前转铁蛋白。转铁蛋白促凝剂
细胞内的活动受各种翻译后机制的动态控制。我们最近的研究
揭示了神经鞘磷脂(SM)在细胞膜外叶中负责维持
Tf处于加密状态,且SM水解会激活Tf并释放Tf微泡(MVS)。SM
新陈代谢在许多疾病中都会改变,包括动脉粥样硬化、糖尿病、败血症和癌症,
同样的疾病环境会导致TF的异常激活。目前的提议是以上述小说为基础的
研究发现并建议探讨SM代谢在调节Tf-
中介止血、血栓形成和炎症。目标1侧重于阐明SM通过
代谢调节TF促凝血活性,而Aim 2研究SM代谢是否
影响止血和血栓形成。目标3中提出的实验将检验这一假设
炎症诱导的SM代谢改变在转铁蛋白激活和转铁蛋白介导中起关键作用
凝血障碍。目标4侧重于研究SM代谢改变是否通过
转铁蛋白活性的调节。在拟议的研究中,我们将操纵巨噬细胞中的SM水平,
内皮细胞,以及其他类型的细胞,通过过度表达或下调涉及的各种酶
在SM代谢中或使用这些酶的特定药理抑制剂。我们将雇佣不同的
SM代谢异常基因敲除小鼠及其止血血栓模型的研究
新发现的机制的病理生理学相关性。我们建议的研究将导致
我们对TF介导的凝血如何在各种疾病环境中被激活的理解发生了范式转变。
它们还可能导致开发新的、有针对性的干预措施来预防血栓形成。
英文摘要
Upon vascular injury, plasma clotting factor VII (FVII) along with traces of activated FVII (FVIIa) come into
contact with the cofactor tissue factor (TF), which is expressed constitutively in cells within the vessel wall.
Complex formation of FVIIa with TF results in a marked enhancement of the catalytic activity of FVIIa and
triggers TF-mediated blood coagulation. Certain disease conditions induce TF expression in circulating blood
cells and vascular endothelial cells and thus allow direct contact between circulating blood and TF that leads
to thrombosis. While TF-mediated blood coagulation is essential to maintain hemostasis, the aberrant
activation of TF-mediated blood coagulation leads to thrombosis, the precipitating event in acute myocardial
infarction, ischemic stroke, and sepsis. Therefore, the proper regulation of TF expression and the activity is
critical for not only to the maintenance of the hemostatic balance but also for health in general. Typically, most
of the TF expressed in cells stays encrypted with very little procoagulant activity that is sufficient to achieve
hemostasis but not to cause intravascular coagulation. Cellular injury enhances TF procoagulant activity
greatly without altering TF antigen levels, i.e., transforming cryptic TF to prothrombotic TF. TF procoagulant
activity in cells is controlled dynamically by a variety of post-translational mechanisms. Our recent studies
revealed that sphingomyelin (SM) in the outer leaflet of the plasma membrane is responsible for maintaining
TF in an encrypted state and that hydrolysis of SM activates TF and releases TF+ microvesicles (MVs). SM
metabolism is altered in many disease settings, including atherosclerosis, diabetes, sepsis, and cancer, the
same disease settings that induce aberrant activation of TF. The current proposal is built on the above novel
findings and proposes to investigate the pathophysiologic relevance of SM metabolism in regulation of TF-
mediated hemostasis, thrombosis, and inflammation. Aim 1 focuses on elucidating mechanisms by which SM
metabolism regulates TF procoagulant activity, whereas Aim 2 investigates whether SM metabolism
influences hemostasis and thrombosis. Experiments proposed in Aim 3 will test the hypothesis that acute
inflammation-induced alterations in SM metabolism play a key role in TF activation and TF-mediated
coagulopathy. Aim 4 focuses on investigating whether altered SM metabolism contributes to inflammation via
the regulation of TF activity. In the proposed studies, we will manipulate SM levels in macrophages,
endothelial cells, and other cell types by the overexpression or down regulation of various enzymes involved
in the SM metabolism or using specific pharmacological inhibitors of these enzymes. We will employ various
knock-out mice with altered SM metabolism and murine models of hemostasis and thrombosis to investigate
the pathophysiologic relevance of the newly identified mechanism. Our proposed studies will lead to a
paradigm shift in our understanding of how TF-mediated coagulation is activated in various disease settings.
They may also lead to the development of novel, targeted interventions to prevent thrombosis.
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