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，作为因子 (F)VII 的高亲和力受体 FVIIa。 TF-FVIIa 复合物是凝血的主要引发剂，在止血中发挥重要作用。 然而，异常的 TF 表达是大多数形式血栓形成的基础。 TF 表达也被诱导响应 作为先天免疫反应的一部分，针对细菌和病毒感染。这个表达可以是保护性的 通过引发弥散性血管内凝血（DIC）来限制病原体或病理的传播。 凝血蛋白酶的 TF 依赖性生成也会导致蛋白酶激活受体的激活 （PAR）。我的实验室在理解 TF、凝固蛋白酶和 PAR 的作用方面做出了重大贡献 用于止血、血栓形成、内毒素血症、缺血再灌注损伤、动脉粥样硬化和病毒感染。这 R35 OIA 申请是 NHLBI 资助的两项 R01 拨款的延伸：静脉血栓形成的机制 胰腺癌;凝血酶 PAR1 途径在病毒感染中的作用。我们已经表明，循环水平 肿瘤来源的 TF+ 细胞外囊泡 (EV) 与静脉血栓栓塞的增加有关 胰腺癌患者。此外，我们发现 TF+ EVs 会增强小鼠的静脉血栓形成 人类胰腺肿瘤。我们还表明，凝血和 PAR1 信号传导的 TF 依赖性激活 通过增强心脏中的抗病毒 IFNβ 通路，对柯萨奇病毒 B3 发挥保护作用。相比之下， PAR1 抑制肺部针对甲型 H1N1 流感感染的病理性 NF-κB 反应。内政部 融资机制将为我们集团提供稳定的资金和更多的时间来追求更高风险 奖励项目，例如对血浆和电动汽车进行蛋白质组分析，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、凝血蛋白酶和 PAR 在癌症中的保护和病理作用 感染。该提案有两个假设： 1/ TF 增强静脉血栓形成和肿瘤生长 在胰腺癌中，2/ TF 依赖性凝血激活既具有保护性反应，又具有病理性反应 到病毒感染。我们将继续研究血栓风险的血浆生物标志物的鉴定 癌症患者使用临床样本。我们将确定导致癌症的促血栓途径—— 使用小鼠模型进行相关血栓形成。此外，我们将确定肿瘤和宿主来源的作用 TF 在小鼠胰腺肿瘤生长中的作用。我们将鉴定小鼠病理性 TF 的细胞来源 病毒感染模型可能会导致预防 DIC 的新疗法。我们将阐明 PAR1 如何发挥保护作用 通过增强心脏中的 IFNβ 抗病毒途径和抑制病理性 NF-κB 途径 肺对病毒感染的反应。这些知识可能会导致血栓形成新生物标志物的鉴定 风险、胰腺癌的治疗以及病毒感染的保护。