Fibrin(ogen) in Abdominal Aortic Aneurysm Pathogenesis

项目总结/摘要 腹主动脉瘤（AAA）导致高达15，000例患者的显著发病率和死亡率 美国的病人。没有有效的药物干预，治疗仅限于手术 在最大扩张点进行干预。这种疾病的发病机制知之甚少， 药物干预的发展困难。纤维蛋白原是一种重要的参与者， 止血、炎症和伤口愈合过程中，已知在AAA患者中升高。但这 观察没有得到充分的调查，没有机制来解释这种海拔一直是 实验鉴定。我们实验室的工作表明，小鼠纤维蛋白原的消耗 模型成功地减弱了AAA的公认动物模型，并减少了炎性细胞因子。 然而，纤维蛋白原介导的AAA发病机制的分子机制仍不清楚。 因此，了解纤维蛋白原耗竭减弱AAA的分子机制， 导致AAA中新的治疗策略。 本提案的主要目的是研究纤维蛋白原导致AAA的机制 发病机制具体来说，我们将研究巨噬细胞与纤维蛋白原的结合如何促进AAA 发病机制，以及纤维蛋白凝块结构和伴随的纤维蛋白溶解抵抗如何促成AAA 发病机制我们假设纤维蛋白原沉积到AAA中加速了动脉瘤的生长， 增加凝血和炎症的激活。这一假设将通过两个 特定的目标和几种独特的小鼠模型。在这些目标中，我们将评估纤维蛋白原对 通过纤维蛋白凝块结构和因子XIII（FXIII;目的1）分析止血作用的AAA， 通过删除纤维蛋白原γ链中的巨噬细胞结合位点的炎症作用（AIM 2）。的 这项工作的长期目标是确定纤维蛋白原在这种疾病过程中的作用。如果成功 完成，确定了一种机制，以解释纤维蛋白原升高的AAA患者。结果从 预计拟议的研究也将大大提高我们目前对AAA的认识 发病机制，并对我们确定AAA治疗可能靶点的能力产生积极影响。这 研究金亦会培训分子生物学和功能基因组学的主要研究员， 在该领域建立研究生涯。

PROJECT SUMMARY/ABSTRACT Abdominal Aortic Aneurysm (AAA) results in significant morbidity and mortality in upwards to 15,000 patients in the United States. No effective pharmaceutical intervention exists and treatment is limited to surgical intervention at the point of maximal expansion. The pathogenesis of this disease is poorly understood, making development of pharmaceutical intervention difficult. The protein fibrinogen, an important participant in hemostatic, inflammatory and wound-healing processes, is known to be elevated in AAA patients. However, this observation has not been adequately investigated, and no mechanism to explain this elevation has been experimentally identified. Work performed in our lab has demonstrated that depletion of fibrinogen in a mouse model successfully attenuates an accepted animal model of AAA, and decreases inflammatory cytokines. However, the molecular mechanism(s) responsible for fibrinogen mediated AAA pathogenesis remains unclear. As such, understanding the molecular mechanism(s) responsible for fibrinogen depletion attenuating AAA could lead to novel therapeutic strategies in AAA. The primary goal of this proposal is investigate the mechanisms by which fibrinogen contributes to AAA pathogenesis. Specifically, we will study how macrophage binding with fibrinogen contributes to AAA pathogenesis, and how fibrin clot structure and accompanying fibrinolytic resistance contributes to AAA pathogenesis. We hypothesize that fibrinogen deposition into AAA accelerates aneurysmal growth by increasing the activation of coagulation and inflammation. This hypothesis will be addressed with two specific aims and several unique mouse models. In these aims, we will assess the influence of fibrinogen on AAA through hemostatic action via analysis of fibrin clot structure and factor XIII (FXIII; aim 1) and inflammatory action via deletion of the macrophage binding site in the fibrinogen gamma chain (aim 2). The long term objective of this work is to identify a role for fibrinogen in this disease process. If successfully completed, identified a mechanism to explain fibrinogen elevation in AAA patients. The outcomes from the proposed studies are expected to have also significantly advanced our current knowledge of AAA pathogenesis, and have a positive impact on our ability to identify possible targets for AAA therapy. This fellowship grant will also train the principle investigator in molecular biology and functional genomics in order to establish a research career in the field.