Tissue factor-dependent coagulation in thrombosis and immune responses

血栓形成和免疫反应中的组织因子依赖性凝血

• 批准号: 10558720
• 负责人: Nigel Mackman
• 金额: $ 93.3万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-01 至 2028-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10558720
• 关键词: Affinity; Atherosclerosis; Bacterial Infections; Biological Assay; Biological Markers; Cancer Patient; Choristoma; Clinical; Coagulation Process; Complex; Coxsackie Viruses; Disseminated Intravascular Coagulation; Endotoxemia; F2R gene; Funding; Funding Mechanisms; Generations; Goals; Grant; Growth; Health; Heart; Hemostatic function; Human; Immune response; Infection; Influenza A Virus, H1N1 Subtype; Influenza A virus; Innate Immune Response; Integral Membrane Protein; Knowledge; Lung; Malignant Neoplasms; Malignant neoplasm of pancreas; Measures; Modeling; Mus; Myocarditis; National Heart, Lung, and Blood Institute; Pathologic; Pathway interactions; Peptide Hydrolases; Plasma; Play; Proteinase-Activated Receptors; Proteomics; Reperfusion Injury; Risk; Risk Marker; Role; Sampling; Signal Transduction; Source; System; Thrombin; Thromboplastin; Thrombosis; Time; Tumor-Derived; Venous Thrombosis; Viral; Virus Diseases; enhancing factor; extracellular vesicles; high reward; high risk; human model; improved; influenza A pneumonia; mouse model; new technology; novel; novel therapeutics; pancreatic cancer patients; pancreatic neoplasm; pathogen; prevent; protein function; receptor; response; thrombotic; tumor; tumor growth; venous thromboembolism

Tissue factor (TF) is a transmembrane protein that functions as a high-affinity receptor for factor (F)VII and FVIIa. The TF-FVIIa complex is the primary initiator of coagulation and plays an essential role in hemostasis. However, aberrant TF expression underlies most forms of thrombosis. TF expression is also induced in response to bacterial and viral infections as part of the innate immune response. This expression can be either protective by limiting the spread of the pathogen or pathologic by triggering disseminated intravascular coagulation (DIC). TF-dependent generation of coagulation proteases also leads to activation of protease-activated receptors (PARs). My lab has made major contributions to understanding the roles of TF, coagulation proteases and PARs in hemostasis, thrombosis, endotoxemia, ischemia-reperfusion injury, atherosclerosis, and viral infections. This R35 OIA application is an extension of two NHLBI funded R01 grants: Mechanism of venous thrombosis in pancreatic cancer; Role of the thrombin PAR1 pathway in viral infection. We have shown that levels of circulating tumor-derived, TF+ extracellular vesicles (EVs) are associated with increased venous thromboembolism in pancreatic cancer patients. In addition, we found that TF+ EVs enhance venous thrombosis in mice bearing human pancreatic tumors. We have also shown that TF-dependent activation of coagulation and PAR1 signaling is protective in response to Coxsackievirus B3 by boosting the antiviral IFNβ pathway in the heart. In contrast, PAR1 suppresses the pathologic NF-κB response in the lung in response to influenza A H1N1 infection. The OIA funding mechanism would provide stable funding and increased time for our group to pursue higher risk-higher reward projects, such as performing proteomic analysis of plasma and EVs, establish new technologies, such as the ExoView system, and following up on exciting discoveries. Our long-term goals are to further understand the protective and pathologic roles of TF, coagulation proteases and PARs in cancer and infections. There are two hypotheses for this proposal: 1/ TF enhances venous thrombosis and tumor growth in pancreatic cancer, and 2/ TF-dependent activation of coagulation is both protective and pathologic in response to viral infection. We will continue our studies on the identification of plasma biomarkers of thrombotic risk in cancer patients using clinical samples. We will identify prothrombotic pathways that contribute to cancer- associated thrombosis using mouse models. In addition, we will determine the roles of tumor and host derived TF in the growth of pancreatic tumors in mice. We will identify the cellular sources of pathologic TF in mouse models of viral infection that may lead to new treatments to prevent DIC. We will elucidate how PAR1 is protective by both enhancing the IFNβ antiviral pathway in the heart and suppressing the pathologic NF-κB pathway in the lung in response to viral infection. This knowledge may lead to the identification of new biomarkers of thrombotic risk, treatments for pancreatic cancer and protection from viral infection.

组织因子（TF）是一种跨膜蛋白，用作因子（F）VII和 fviia。 TF-FVIIA复合物是凝血的主要引发剂，在止血中起着至关重要的作用。 但是，异常的TF表达是大多数形式的血栓形式的基础。 TF表达也被诱导 作为先天免疫反应的一部分，细菌和病毒感染。该表达可以受到保护 通过触发散布的血管内凝血（DIC）来限制病原体或病理的扩散。 凝结蛋白酶的TF依赖性产生也导致蛋白酶激活受体的激活 （pars）。我的实验室为理解TF，凝结蛋白酶和Pars的作用做出了重大贡献 在止血，血栓形成，内毒素血症，缺血 - 灌注损伤，动脉粥样硬化和病毒感染。这 R35 OIA应用是两个NHLBI资助的R01补助金的扩展：静脉血栓形成机理 胰腺癌;凝血酶PAR1途径在病毒感染中的作用。我们已经证明了循环的水平 肿瘤来源的TF+细胞外蔬菜（EV）与静脉血栓栓塞增加有关 胰腺癌患者。此外，我们发现TF+ EVS增强了轴承小鼠的静脉血栓形成 人胰腺肿瘤。我们还表明，凝结和PAR1信号的激活依赖于TF 通过促进心脏中的抗病毒IFNβ途径来应对Coxsackievivirus B3的响应。相比之下， PAR1抑制肺中肺中的病理NF-κB反应，以响应影响力H1N1感染。 OIA 资金机制将为我们的小组提供更高风险高的时间提供稳定的资金和增加的时间 奖励项目，例如对等离子体和电动汽车进行蛋白质组学分析，建立新技术，例如 作为Exoview系统，并跟进令人兴奋的发现。我们的长期目标是进一步 了解TF，凝结蛋白酶和PAR在癌症和PAR中的保护和病理作用 感染。该提议有两个假设：1/ TF增强静脉血栓形成和肿瘤生长 在胰腺癌中，凝血的2/ TF依赖性激活既受保护，又受到病理的响应 感染病毒。我们将继续研究血栓形成风险等离子体生物标志物的研究 癌症患者使用临床样本。我们将确定有助于癌症的促血栓形成途径 使用小鼠模型相关的血栓形成。此外，我们将确定肿瘤和宿主的作用 TF在小鼠胰腺肿瘤的生长中。我们将确定小鼠病理TF的细胞来源 病毒感染的模型可能导致新的治疗方法以防止DIC。我们将阐明如何保护PAR1 通过增强心脏中的IFNβ抗病毒途径并抑制病理NF-κB途径 响应病毒感染的肺。这些知识可能导致鉴定血栓形成的新生物标志物 风险，胰腺癌的治疗方法以及免受病毒感染的保护。