Fibrin(ogen) in Abdominal Aortic Aneurysm Pathogenesis

腹主动脉瘤发病机制中的纤维蛋白（原）

• 批准号: 10006344
• 负责人: Hannah Russell
• 金额: $ 3.82万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10006344
• 关键词: Abdominal Aortic Aneurysm; Active Sites; Acute-Phase Proteins; Address; American; Aneurysm; Angiotensin II; Animal Model; Aorta; Attenuated; Binding; Binding Sites; Biochemical; Biomechanics; Caliber; Cardiovascular Diseases; Cleaved cell; Coagulation Process; Cytokine Activation; Data; Deposition; Development; Diagnosis; Disease; Enzymes; Epidemiology; Factor XIII; Fellowship; Fiber; Fibrin; Fibrinogen; Fibrinolysis; Fostering; Functional disorder; Generations; Genetic; Genetic Polymorphism; Goals; Grant; Growth; Hemostatic Agents; In Vitro; Inflammation; Inflammatory; Intervention; Knowledge; Lead; Leukocytes; Link; Macrophage Activation; Mediating; Mediator of activation protein; Metabolic; Molecular; Molecular Biology; Morbidity - disease rate; Mus; Operative Surgical Procedures; Outcome; Participant; Pathogenesis; Pathology; Patients; Pattern; Pharmacologic Substance; Plasma; Polymers; Process; Proteins; Public Health; Research; Research Personnel; Resistance; Role; Ruptured Aneurysm; Structure; Testing; Thick; Thrombin; Thrombus; Training; Treatment Protocols; United States; Work; base; cardiovascular risk factor; career; crosslink; cytokine; fibrinopeptides gamma; functional genomics; gain of function; macrophage; mortality; mouse model; novel; novel therapeutics; recruit; wound healing

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.

项目摘要/摘要 腹主动脉瘤（AAA）导致高达15,000 美国的患者。不存在有效的药物干预，治疗仅限于手术 在最大膨胀点的干预。这种疾病的发病机理知之甚少，使得 制药干预的开发困难。蛋白质纤维蛋白原，重要参与者 已知在AAA患者中，止血，炎症和伤口治疗过程已升高。但是，这个 观察结果尚未得到充分研究，没有任何解释这种海拔的机制 实验确定。在我们的实验室中进行的工作证明了小鼠纤维蛋白原的耗竭 模型成功地减弱了AAA的动物模型，并降低了炎性细胞因子。 但是，负责纤维蛋白原介导的AAA发病机理的分子机制尚不清楚。 因此，了解负责纤维蛋白原耗竭衰减AAA的分子机制可能 导致AAA的新型治疗策略。 该提案的主要目标是研究纤维蛋白原有助于AAA的机制 发病。具体而言，我们将研究巨噬细胞与纤维蛋白原的结合如何有助于AAA 发病机理，以及纤维蛋白凝块结构和伴随的纤维蛋白耐药性有助于AAA 发病。我们假设纤维蛋白原沉积到AAA中可以通过 增加凝血和炎症的激活。这个假设将通过两个 具体目标和几种独特的鼠标模型。在这些目标中，我们将评估纤维蛋白原对 通过分析纤维蛋白凝块结构和因子XIII（FXIII； AIM 1）和 通过缺失纤维蛋白原γ链中巨噬细胞结合位点的炎症作用（AIM 2）。这 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，确定了一种解释AAA患者纤维蛋白原升高的机制。来自 预计拟议的研究也将显着提高我们目前对AAA的了解 发病机理，对我们识别AAA治疗靶标的能力产生积极影响。这 奖学金赠款还将培训分子生物学和功能基因组学的主要研究者，以便为了 在该领域建立研究职业。