Fibrin(ogen) Structure and Interactions

纤维蛋白（原）结构和相互作用

• 批准号: 8719152
• 负责人: LEONID V. MEDVED
• 金额: $ 38.74万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-01-01 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8719152
• 关键词: Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Binding; Binding Sites; Biochemical; Blood Circulation; Cardiovascular Diseases; Cell Communication; Cell-Cell Adhesion; Coagulation Process; Complex; Data; Development; Endothelial Cells; Endothelium; Fibrin; Fibrinogen; Fibrinolysis; Functional disorder; Funding; Goals; Hemostatic function; Infarction; Inflammation; Inflammatory; Inflammatory Response; Intercellular adhesion molecule 1; Knowledge; Leukocytes; Maps; Mediating; Molecular; Myocardial; Myocardial Ischemia; N Domain; N-terminal; Pathogenesis; Pathologic Processes; Peptides; Pharmacia brand of estropipate; Physiological Processes; Plasma Proteins; Play; Process; Property; Proteins; Recombinants; Reperfusion Injury; Reperfusion Therapy; Research; Role; Signal Transduction; Site; Structure; Techniques; Testing; Thrombosis; Triglyceride Metabolism; VLDL receptor; Wound Healing; angiogenesis; atherogenesis; base; biophysical techniques; cadherin 5; cell motility; cell type; drug candidate; fibrin receptor; in vivo; in vivo Model; inhibitor/antagonist; migration; mimetics; mouse model; novel; novel therapeutics; polymerization; public health relevance; receptor; tumorigenesis

DESCRIPTION (provided by applicant): Fibrinogen is a multifunctional plasma protein that after conversion into fibrin contributes to hemostasis and other physiological and pathological processes through its interaction with different proteins and cell types. Among these processes is inflammation, which plays a pivotal role in the pathophysiology of cardiovascular diseases. Recruitment of leukocytes from the circulation to sites of inflammation is an integral part of the inflammatory response and transendothelial migration of leukocytes is a key step in such recruitment. Numerous data indicate that fibrinogen is involved in this process. According to the proposed hypotheses, fibrinogen or its degradation products induce leukocyte transmigration by bridging leukocytes to the endothelium through the interaction with the endothelial receptors ICAM-1 or VE-cadherin, respectively. We have recently discovered that fibrin ¿N-domains interact with the VLDL receptor (VLDLR), another receptor on endothelial cells, and this interaction also promotes leukocyte transmigration. Based on this discovery and some preliminary data, we hypothesize that fibrin promotes transendothelial migration of leukocytes through its interaction with VLDLR and such fibrin-induced VLDLR-dependent leukocyte transmigration can be modulated by specific inhibitors targeting this interaction. The major goal of the present application is to test this hypothesis. This will be accomplished in the following specific aims. The first aim is to further prove that fibrin-VLDLR interaction promotes leukocyte transmigration by studying the effect of fibrin on this process. The second aim is to establish the molecular mechanism of this interaction by mapping the complementary binding sites using recombinant techniques and characterizing the interaction between them using biochemical and biophysical methods. The third aim is to develop novel specific inhibitors of this interaction based on knowledge obtained and test their anti-inflammatory properties and cardioprotective effect using in vivo mouse models. The proposed study will clarify the molecular mechanisms of fibrin-dependent inflammation and may result in novel therapeutics for treatment of inflammation-related cardiovascular diseases including myocardial ischemia-reperfusion injury.

描述（由申请方提供）：纤维蛋白原是一种多功能血浆蛋白，转化为纤维蛋白后，通过与不同蛋白质和细胞类型的相互作用，有助于止血和其他生理和病理过程。在这些过程中，炎症在心血管疾病的病理生理学中起着关键作用。白细胞从循环中募集到炎症部位是炎症反应的组成部分，白细胞的跨内皮迁移是这种募集的关键步骤。许多数据表明，纤维蛋白原参与了这一过程。根据所提出的假设，纤维蛋白原或其降解产物通过分别与内皮受体ICAM-1或VE-钙粘蛋白相互作用将白细胞桥接至内皮来诱导白细胞迁移。我们最近发现，纤维蛋白N-结构域与VLDL受体（VLDLR），内皮细胞上的另一种受体相互作用，这种相互作用也促进白细胞的迁移。基于这一发现和一些初步数据，我们假设纤维蛋白通过与VLDLR的相互作用促进白细胞的跨内皮迁移，并且这种纤维蛋白诱导的VLDLR依赖性白细胞迁移可以通过针对这种相互作用的特异性抑制剂来调节。本申请的主要目标是测试该假设。这将通过以下具体目标来实现。第一个目的是通过研究纤维蛋白对这一过程的影响，进一步证明纤维蛋白-VLDLR相互作用促进白细胞迁移。第二个目标是建立 通过使用重组技术绘制互补结合位点并使用生物化学和生物物理方法表征它们之间的相互作用，来研究这种相互作用的分子机制。第三个目的是开发新的特定的抑制剂，这种相互作用的基础上获得的知识和测试其抗炎特性和心脏保护作用，使用体内小鼠模型。这项研究将阐明纤维蛋白依赖性炎症的分子机制，并可能为治疗炎症相关的心血管疾病（包括心肌缺血-再灌注损伤）提供新的治疗方法。