SUPPRESSION OF ANTICOAGULANT FACTORS

抑制抗凝因子

• 批准号: 3293272
• 负责人: FLETCHER B TAYLOR
• 金额: $ 24.15万
• 依托单位: OKLAHOMA MEDICAL RESEARCH FOUNDATION
• 依托单位国家: 美国
• 财政年份: 1986
• 资助国家: 美国
• 起止时间: 1986-12-01 至 1992-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3293272
• 关键词: Escherichia coli; Escherichia coli infections; baboons; blood coagulation; blood disorder diagnosis; clotting factor; coagulation factor V; complement; diagnosis design /evaluation; early diagnosis; flow cytometry; fluoresceins; inflammation; interleukin 1; microangiography; monoclonal antibody; platelets; protein C; protein S; receptor; thrombin; thromboplastin; tissue /cell culture; tumor necrosis factor alpha; vascular endothelium

These studies focus on the suppression of anticoagulant factors by inflammatory mediators. We hypothesize that 1) C4bBP in responding to E. coli binds protein S favoring both coagulation and amplification of inflammation (TNF). 2) TNF/Il-1 in responding to E. coli likewise suppresses thrombomodulin favoring both coagulation and amplification of inflammation. We believe that this suppression of the regulatory activity of the anticoagulant factors is reflected by the fall of proteins C and S concentrations following E. coli infusion and bears directly on survival and on the relative resistance to rescue therapy with activated protein C. We propose to test these hypotheses by specifically modifying the response to E. coli of each of these putative components using monoclonal antibodies against protein S, thrombomodulin, C4bBP, TNF, Il-1 and using regulatory proteins including protein S, C4bBP, and activated protein C. Finally, we propose to use this information to design optimal therapeutic schedules. Using the appropriate monoclonal antibodies or regulatory proteins, we will pursue the following aims: In Aim 1, we will examine the role of C4bBP and its interactions with protein S in the acute response to LD100 E. coli. We also will examine whether this C4bBP-protein S interaction influences the inflammatory response (TNF). In Aim 2, we will study whether thrombomodulin as well as protein S is suppressed in response to LD100 E. coli and whether TNF and Il-1 play a role in this phenomena. In Aim 3, we will study the role of complement and the response of platelets to LD100 E. coli. Anti-TNF and anti-tissue factor antibodies protect but only attenuate the coagulopathic response 50%. Activation of complement therefore may play a role in promoting expression of coagulant activity of both platelets and endothelium. We examine this possibility by analysis of complement (C5b-9) and prothrombinase factor V assembly on activated platelets by flow cytometry using the appropriate fluorescein labeled antibodies. In Aim 4, we will study whether C4bBP and TNF/Il-1 play a role in the subacute responses to E. coli. This question is addressed using a model of the microangiopathic response recently developed in our laboratory. In Aim 5 we will apply the information gained in Aims 1-4 to the design of tests for early diagnosis and more effective activated protein C therapy.

这些研究集中在抑制抗凝因子， 炎症介质。 我们推测：（1）C4 bBP在E. 大肠杆菌结合蛋白S，有利于凝固和扩增 炎症（TNF）。2)TNF/IL-1对E.大肠杆菌同样 抑制血栓调节蛋白，有利于凝血和扩增 炎症 我们认为这种对监管活动的抑制 抗凝血因子的变化反映在蛋白C和S的下降上 浓度后E.大肠杆菌的输注，直接关系到生存 以及对用活化蛋白C进行的挽救治疗的相对抗性。 我们建议通过专门修改响应来测试这些假设 与大肠使用单克隆抗体， 针对蛋白S、血栓调节蛋白、C4 bBP、TNF、IL-1，并使用调节 蛋白质包括蛋白质S、C4 bBP和活化蛋白质C。 最后我们 建议使用这些信息来设计最佳的治疗方案。 使用适当的单克隆抗体或调节蛋白，我们将 追求以下目标：在目标1中，我们将研究C4 bBP的作用， 在对LD 100 E的急性反应中与蛋白S的相互作用。杆菌 我们 还将研究C4 bBP-蛋白S相互作用是否影响 炎症反应（TNF）。 在目标2中，我们将研究 血栓调节蛋白以及蛋白S响应于LD 100 E而被抑制。 以及TNF和IL-1是否在这一现象中起作用。 在目标3中，我们 将研究补体的作用和血小板对LD 100 E的反应。 杆菌 抗肿瘤坏死因子和抗组织因子抗体保护，但只有 使凝血病反应减弱50%。 补体的活化 因此，可能在促进表达凝血活性方面起作用， 血小板和内皮细胞。 我们通过分析来研究这种可能性， 补体（C5 b-9）和凝血酶原酶因子V组装 使用适当的荧光素标记的流式细胞术检测血小板 抗体的 目的4：探讨C4 bBP和TNF/IL-1在胃癌发生发展中的作用 在E.杆菌 这个问题是用一个 我们最近开发的微血管病反应模型 实验室 在目标5中，我们将把目标1-4中获得的信息应用于 早期诊断和更有效的激活测试的设计 蛋白C疗法