Fibrin(ogen) Structure and Interactions

描述（由申请人提供）：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一个组成部分，白细胞的跨内皮迁移是这种募集的关键步骤。大量数据表明纤维蛋白原参与了这一过程。根据提出的假设，纤维蛋白原或其降解产物分别通过与内皮受体ICAM-1或VE-cadherin相互作用，将白细胞桥接到内皮，从而诱导白细胞迁移。我们最近发现纤维蛋白¿n结构域与内皮细胞上的另一种受体VLDL受体（VLDLR）相互作用，这种相互作用也促进白细胞的转运。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依赖性白细胞的迁移可以通过靶向这种相互作用的特异性抑制剂来调节。本应用程序的主要目标是检验这一假设。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在白细胞转运过程中的作用，进一步证明纤维蛋白- vldlr相互作用促进白细胞转运。第二个目标是建立

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.