Imaging Endocarditis

心内膜炎影像学检查

基本信息

批准号：
7693804
负责人：
Peter Rolf Panizzi
金额：
$ 0.23万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-01 至 2009-09-15
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7693804
关键词：
Accounting Active Sites Acute Address Adult Age Animals Antibiotic Therapy Antigens Area Argatroban Bacteremia Bacteria Bacterial Endocarditis Bacterial Infections Binding Blood Blood Platelets C-terminal C57BL/6 Mouse Catheters Cause of Death Cell surface Cells Chronic Cleaved cell Clinical Coagulase Coagulation Process Complex Development Diagnosis Echocardiography Endocarditis Endothelial Cells Endothelium Environment Enzyme Precursors Fibrin Fibrinogen Flow Cytometry Generations Goals Heart Heart Valves ITGAM gene Image Immune In Vitro Incidence Infection Injury Label Lesion Mechanics Mediating Mediator of activation protein Modeling Molecular Monitor Monocytosis Mus N-terminal Neonatal Outcome Pathogenesis Pathology Patients Property Prothrombin Publishing Recruitment Activity Repetitive Sequence Research Roentgen Rays Role Rolfing Staphylocoagulase Staphylococcus aureus Structure Surface Tandem Repeat Sequences Testing Thrombin Thromboplastin Tissues Virulence Factors Wound Healing analog base human disease imaging modality improved in vivo inhibitor/antagonist insight macrophage molecular imaging monocyte mortality novel resistant strain response small molecule success

项目摘要

DESCRIPTION (provided by applicant): The long-term goal of this proposed research is to define the molecular mechanism of vegetation formation during acute bacterial endocarditis (ABE), a potentially deadly human disease caused by bacterial infection of the valves of the heart. The leading cause of deaths from ABE is associated with coagulase-positive Staphylococcus aureus infections which account for 40-50% of neonatal endocarditis and 30-40% of endocarditis in adults between the ages of 16-60 years, with a mortality rate of 25-47%, even with antibiotic therapy. It is our hypothesis that S. aureus bacteremia induces expression of Ly6CHi monocytes leading to increased bacterial attachment to the heart valve surface. S. aureus expresses staphylocoagulase, a bifunctional molecule that activates prothrombin by N-terminal domains and mediates staphylocoagulaseprothrombin complex tethering to the growing vegetations by C-terminal tandem repeats that bind multiple fibrinogen molecules. Novel prothrombin analogs developed in this proposal are hypothesized to localize to the surface of the growing vegetations during ABE and provide new specific probes to monitor S. aureus ABE development, through powerful in vivo molecular imaging methods. Clinical imaging of endocarditis is performed by transesophageal echocardiogram, which is often difficult to interpret due to poor images and variable bacterial attachment. It is our contention that the use of these novel-imaging agents will be directly translatable to the clinical environment and ultimately, led to improved patient outcomes. The hypotheses proposed above will be tested by the following specific aims: Aim 1. To characterize monocyte response to S. aureus-mediate ABE and to define the role of these cells in vegetation formation, Aim 2. To determine the localization of active site labeled prothrombin in vivo during S. aureus endocarditis, and Aim 3. To characterize the effect of argatroban on the development of fibrin-bacteria-platelet vegetations during ABE.

描述（由申请人提供）：这项拟议研究的长期目标是确定急性细菌性心内膜炎（ABE）期间赘生物形成的分子机制，这是一种由心脏瓣膜细菌感染引起的潜在致命的人类疾病。 ABE 死亡的主要原因与凝固酶阳性金黄色葡萄球菌感染有关，该感染占新生儿心内膜炎的 40-50% 和 16-60 岁成人心内膜炎的 30-40%，死亡率为 25% -47%，即使采用抗生素治疗。我们的假设是金黄色葡萄球菌菌血症诱导 Ly6CHi 单核细胞的表达，导致细菌附着到心脏瓣膜表面增加。金黄色葡萄球菌表达葡萄球菌凝固酶，这是一种双功能分子，通过 N 端结构域激活凝血酶原，并通过结合多个纤维蛋白原分子的 C 端串联重复序列介导葡萄球菌凝固酶凝血酶原复合物与生长的植被结合。假设本提案中开发的新型凝血酶原类似物在 ABE 期间定位于生长的植被表面，并通过强大的体内分子成像方法提供新的特异性探针来监测金黄色葡萄球菌 ABE 的发育。心内膜炎的临床影像学是通过经食管超声心动图进行的，但由于图像质量差和细菌附着多变，通常难以解释。我们的观点是，这些新型成像剂的使用将直接转化为临床环境，并最终改善患者的治疗结果。上述假设将通过以下具体目标进行检验：目标 1. 表征单核细胞对金黄色葡萄球菌介导的 ABE 的反应，并定义这些细胞在植被形成中的作用，目标 2. 确定标记的活性位点的定位金黄色葡萄球菌心内膜炎期间体内凝血酶原，目标 3. 表征阿加曲班对 ABE 期间纤维蛋白-细菌-血小板赘生物发育的影响。