The Evolution of Endocardial Thrombosis in Heart Failure

心力衰竭心内膜血栓形成的演变

• 批准号: 8075478
• 负责人: ANTONY Y KIM
• 金额: $ 12.44万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-01 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8075478
• 关键词: Adenovirus Vector; Anticoagulants; Biology; Cardiac; Cardiovascular system; Cells; Chronic; Coagulation Process; Commit; Complication; Data; Development; Dilated Cardiomyopathy; Disease; Down-Regulation; Endocardium; Endothelium; Equilibrium; Evolution; Failure; Gene Delivery; Gene Expression; Goals; Heart; Heart failure; Homeostasis; In Vitro; Inflammatory; Laboratories; Lead; Link; Mechanical Stress; Modeling; Molecular; Morbidity - disease rate; Mus; Nature; Oryctolagus cuniculus; Pathway interactions; Patients; Physicians; Plasma; Play; Principal Investigator; Property; Protein C; Research; Research Personnel; Research Project Grants; Risk; Role; Scientist; Signal Transduction; Source; Stimulus; Stress; Surface; System; TFPI; Therapeutic; Thrombin; Thrombomodulin; Thromboplastin; Thrombosis; Translational Research; United States; Vascular Endothelium; Work; abstracting; activated Protein C; in vitro Model; in vivo; in vivo Model; indexing; mortality; pressure; programs; protein expression; receptor; research study; restoration; skills; treatment strategy

DESCRIPTION (provided by applicant): This K08 application focuses on the thrombosis which occurs as a common and severe complication in chronic heart failure (CHF), a major source of morbidity and mortality in the U.S. Recent evidence has linked CHF with a hypercoagulable state as demonstrated by elevated indices of thrombin and tissue factor (TF) activation. Both thrombin and TF play a critical role in the formation of clot and thrombotic complications on the endothelial surface, however, their role in thrombosis in CHF is currently unclear. The Principal Investigator has proposed a comprehensive five-year research program that will focus on the procoagulant and anticoagulant molecules on the endocardium in the prothrombotic state of chronic heart failure (CHF). This proposal builds upon exciting preliminary data generated in our laboratory which has led to a working hypothesis that the biophysical and inflammatory conditions in CHF lead to a loss of thromboresistance in the failing heart. We will examine whether the condition of heart failure alters endocardia! anticoagulant-procoagulant homeostasis such that these changes are associated with increased thrombogenicity. Specific Aim #1 will provide careful in vivo analysis of anticoagulant and procoagulant molecules on the endocardium and the functional consequences of altered anticoagulantprocoagulant homeostasis. Specific Aim #2 will examine in vitro underlying molecular mechanisms of altered homeostasis determined in inflammatory- and mechanically-stressed murine endocardium. Finally, Specific Aim #3 will explore in vivo strategies to restore homeostasis on the endocardium using adenoviral gene delivery and exogenous activated protein C. In summary, our studies will elucidate the critical role of the endocardium in maintaining anticoagulant-procoagulant homeostasis and how CHF alters this balance. This research project will synthesize experiments already familiar to the Principal Investigator and his sponsor's laboratory as well as new experiments and skills that are vital to the Pi's development as a physician scientist. These results may lead to a shift in our current understanding of thrombosis in CHF and potentially lead to strategies which would directly impact patients with CHF at risk for thrombosis. Chronic heart failure is an extremely common disease in the United States with over 5 million cases. Thromboembolic disease is a significant problem in patients with CHF. Elucidating the mechanisms underlying the procoagulant nature of CHF could greatly reduce the associated morbidity and mortality. (End of Abstract)

描述（由申请人提供）： 本K 08申请关注血栓形成，血栓形成是慢性心力衰竭（CHF）的常见和严重并发症，是美国发病率和死亡率的主要来源。最近的证据表明，CHF与高凝状态有关，如凝血酶和组织因子（TF）活化指数升高所示。凝血酶和TF在内皮表面的凝块形成和血栓形成并发症中起关键作用，然而，它们在CHF血栓形成中的作用目前尚不清楚。主要研究者提出了一个全面的五年研究计划，将重点放在慢性心力衰竭（CHF）血栓前状态的促凝血和抗凝分子上。这一建议建立在我们实验室产生的令人兴奋的初步数据基础上，这些数据导致了一个工作假设，即CHF中的生物物理和炎症条件导致衰竭心脏中血栓阻力的丧失。我们将检查心力衰竭的情况是否会改变心内膜！抗凝-促凝体内平衡，使得这些变化与血栓形成性增加有关。具体目标#1将提供抗凝剂和促凝剂分子对内皮细胞的仔细的体内分析，以及抗凝剂和促凝剂稳态改变的功能后果。具体目标#2将检查在炎症和机械应激的鼠内皮细胞中确定的改变的稳态的体外潜在分子机制。最后，具体目标#3将探索使用腺病毒基因递送和外源性活化蛋白C恢复内分泌稳态的体内策略。总之，我们的研究将阐明内皮素在维持抗凝-促凝血稳态中的关键作用，以及CHF如何改变这种平衡。该研究项目将综合主要研究者及其赞助商实验室已经熟悉的实验，以及对Pi作为医生科学家的发展至关重要的新实验和技能。这些结果可能导致我们目前对CHF血栓形成的理解发生转变，并可能导致直接影响CHF患者血栓形成风险的策略。慢性心力衰竭在美国是一种非常常见的疾病，有超过500万例。血栓栓塞性疾病是CHF患者的一个重要问题。阐明CHF的促凝血机制可以大大降低相关的发病率和死亡率。 (End摘要）