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的高亲和力受体发挥作用， FVIIa。TF-FVIIa复合物是凝血的主要引发剂，并在止血中发挥重要作用。 然而，TF表达异常是大多数血栓形成的基础。TF表达也被诱导， 细菌和病毒感染作为先天免疫反应的一部分。这种表达可以是保护性的， 通过限制病原体的传播或通过触发弥散性血管内凝血（DIC）而病理性地抑制。 TF依赖性凝血蛋白酶的产生也导致蛋白酶激活受体的激活 （PARs）。我的实验室在理解TF、凝血蛋白酶和PAR的作用方面做出了重大贡献 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申请是两个NHLBI资助的R 01赠款的延伸： 胰腺癌;凝血酶PAR 1通路在病毒感染中的作用。我们已经证明， 肿瘤来源的TF+细胞外囊泡（EV）与静脉血栓栓塞增加相关， 胰腺癌患者。此外，我们发现TF+ EV增强了小鼠的静脉血栓形成， 人类胰腺肿瘤我们还发现TF依赖的凝血激活和PAR 1信号传导 通过增强心脏中的抗病毒IFNβ途径，对柯萨奇病毒B3有保护作用。与此相反， PAR 1抑制肺中对甲型流感H1 N1感染的病理性NF-κB反应。内审办 融资机制将提供稳定的资金和更多的时间，我们的集团追求更高的风险-更高 奖励项目，例如对血浆和电动汽车进行蛋白质组学分析，建立新技术， 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.有两种假说：1/ TF促进静脉血栓形成和肿瘤生长 在胰腺癌中，2/TF依赖性凝血激活在应答中既是保护性的，也是病理性的 病毒感染。我们将继续研究血栓形成风险的血浆生物标志物， 癌症患者使用临床样本。我们将找出导致癌症的血栓前通路- 相关的血栓形成。此外，我们将确定肿瘤和宿主衍生的作用， TF在小鼠胰腺肿瘤生长中的作用我们将确定病理性TF的细胞来源在小鼠 病毒感染模型可能会带来预防DIC的新治疗方法。我们将阐明PAR 1是如何保护 通过增强心脏中的IFNβ抗病毒途径和抑制心脏中的病理性NF-κB途径， 肺对病毒感染的反应。这些知识可能会导致新的血栓性生物标志物的鉴定 风险，胰腺癌的治疗和防止病毒感染。