Novel Biomarkers in Aortic Aneurysms and Acute Aortic Dissection

主动脉瘤和急性主动脉夹层的新型生物标志物

• 批准号: 7935405
• 负责人: Harry C., III Dietz
• 金额: $ 49.82万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7935405
• 关键词: Accounting; Acute; Address; Adult; Aneurysm; Animal Model; Antibodies; Aorta; Aortic Aneurysm; Aortic Diseases; Aortic Rupture; Architecture; Area; Authorization documentation; Baltimore; Biological Assay; Biological Markers; Biology; Blood; Blood Vessels; Blood flow; C-reactive protein; Cardiovascular Diseases; Cardiovascular system; Cause of Death; Cessation of life; Chest Pain; Child; Childhood; Cities; Clinical; Clinical Data; Connective Tissue Diseases; Coronary artery; Developed Countries; Development; Diagnosis; Diagnostic Procedure; Disease; Dissection; Economics; Employment; Enrollment; Event; Family; Functional disorder; Growth; Hour; Human; Image; Immunoassay; Individual; Inflammation; Inherited; Injury; Institution; Lead; Life; Losartan; Marfan Syndrome; Maryland; Mass Spectrum Analysis; Measurement; Measures; Methods; Modeling; Molecular; Molecular Profiling; Monitor; Mus; Myocardial Ischemia; Occupations; Operative Surgical Procedures; Pathogenesis; Pathology; Pathway interactions; Patient Care; Patients; Plasma; Plasma Proteins; Play; Population; Predisposing Factor; Process; Protein Isoforms; Proteins; Proteomics; Publishing; Registries; Relative (related person); Risk; Role; Rupture; Ruptured Aortic Aneurysms; Saliva; Sampling; Serum; Signal Transduction; Staging; Stream; Techniques; Technology; Technology Assessment; Testing; Therapeutic; Thoracic aorta; Time; Transforming Growth Factor beta; Transforming Growth Factors; Validation; Wild Type Mouse; Work; aortic valve; base; candidate marker; clinically relevant; insight; mortality; mouse model; novel; outcome forecast; patient population; public health relevance; tool

DESCRIPTION (provided by applicant): This application addresses broad Challenge Area (06) "Enabling Technologies" and specific Change Topic, 06- HL-101 "Developing technologies for assessment of aortic aneurysms prone to rupture or dissection". Aortic dissection describes a tear in the wall of the main vessel in the body, the aorta. The underlying pathology is diverse and predisposing factors include aortic aneurysms and diseases of the connective tissue. This is a life-threatening event, especially if the dissection is located in the ascending part of the thoracic aorta since it may lead to global myocardial ischemia by compromising the aortic valve and blood flow through the coronary arteries. Rupture of the aorta is more rare but almost always associated with a 100% mortality. In the current proposal we address a clinically relevant and pressing need to elucidate the mechanisms that (i) would enable us to identify the patient at risk for a dissection among patients with known aortic aneurysms (ii) facilitate diagnosis of aortic dissection in the patient with acute chest pain and (iii) helps us to individualize therapy. Dilation of the aorta is caused by a multitude of mechanisms including inherited connective tissue disorders such as Marfan syndrome (MFS). We will use MFS as a model for aortic diseases in the current proposal since we have already shown that a comprehensive understanding of this disorder provides greater understanding of vascular wall biology and identifies pathways relevant to aortic aneurysms and dissection in general. In 2006, we showed that excessive TGFbeta signaling plays a major role in the pathogenesis of MFS in a mouse model for MFS. Several candidate markers have been identified by de novo discovery, with one of them being TGFbeta. We could prove that blocking the TGFbeta pathway in the mouse with losartan, an AT1-anatgonist, normalizes aortic wall architecture. We recently demonstrated that circulating TGFbeta levels in the mouse model are significantly higher than in wild-type mice. Furthermore, levels of circulating TGFbeta are decreased by administration of losartan. Recently published results of adding losartan to standard therapy in a pediatric population demonstrated a significant decrease in aortic growth rate. Johns Hopkins is part of the GenTAC registry, which enrolls patients with aortic aneurysms from a broad spectrum of heritable disorders. Recently, we obtained permission to analyze the first 207 patients with MFS enrolled in the registry for levels of TGFbeta and could demonstrate a highly significant increase compared to control patients. In the current proposal we will (Aim 1) continue our discovery work in the mouse model for MFS and validate our candidate marker in the mice as well as the GenTAC population using immunoassays and MRM, a mass spectrometry based breakthrough technology that allows for antibody-independent quantification. In a second step (Aim 2), we established an acute aortic dissection model in the mouse. This will enable us to expand de novo discovery to the acute setting and bridge the gap to biomarker discovery in the patient with acute dissection. We will validate our candidate markers using immunoassays and MRM and thereby gain further insight into prognosis of aortic dissection. As the TGFbeta family has been shown to play a key role in the development of MFS, we aim to develop a multiplex assay (Aim 3) with the ability to measure TGFbeta-1, -2 and - 3 simultaneously in a limited amount of sample. We recently gained the ability to measure TGFbeta in saliva. This might be an attractive option to "screen" patients for the activity of the aneurysm and provide guidance for the therapy in the individual patient. As many aspects of aortic disease, including diagnostic procedures and therapeutic measures, in patients with connective tissue disease are similar to those with a non-syndromatic background, insights from the current projects will contribute to the care for patients with aortic disease in general. Every year Johns Hopkins Institutions directly generate about $10 billion in economic activity in the State of Maryland, a 43% increase from the $7 billion generated in 2002 and the equivalent of one of every twenty-four dollars in the state's economy today. In 2008, Johns Hopkins Institutions provided 45,000 jobs and created 700 new jobs each year since 2002. Directly and indirectly Johns Hopkins Institutions support more than 100,000 jobs in Maryland, one of every 29 in the state. In Baltimore City alone Johns Hopkins directly and indirectly supports 60,000 jobs, or 16.7% of all City employment. PUBLIC HEALTH RELEVANCE: Acute dissections and ruptures of aortic aneurysms comprise for 1-2% of all deaths in industrialized countries. There is a pressing clinical need to find mechanisms that will (i) enable us to identify the patient at risk for a dissection among patients with known aortic aneurysms (ii) facilitate diagnosis of aortic dissection in the patient with acute chest pain and (iii) help us to individualize therapy. The current proposal will use proteomics techniques in an advanced animal model of aortic aneurysms and dissections to gain insight into these mechanisms and validate the findings in a large population of patients with aortic diseases.

描述(由申请人提供)：本申请涉及广泛的挑战领域(06)“使能技术”和具体的变更主题，06-HL-101“开发评估容易破裂或夹层的主动脉瘤的技术”。主动脉夹层描述的是人体主要血管--主动脉壁上的撕裂。潜在的病理是多样的，诱因包括主动脉瘤和结缔组织疾病。这是一个危及生命的事件，特别是如果夹层位于胸主动脉的上升部分，因为它可能会损害主动脉瓣和通过冠状动脉的血液流动，导致全局心肌缺血。主动脉破裂较为罕见，但几乎总是与100%的死亡率相关。在目前的提案中，我们解决了临床上相关的迫切需要，以阐明以下机制：(I)使我们能够在已知的主动脉瘤患者中识别有夹层的患者，(Ii)便于诊断有急性胸痛的患者的主动脉夹层，以及(Iii)帮助我们个体化治疗。主动脉扩张是由多种机制引起的，包括遗传性结缔组织疾病，如马凡综合征(MFS)。在目前的方案中，我们将使用MFS作为主动脉疾病的模型，因为我们已经表明，对这种疾病的全面了解有助于更好地了解血管壁生物学，并确定与主动脉瘤和夹层相关的一般途径。2006年，我们在一种MFS小鼠模型中证明了过度的TGFbeta信号在MFS的发病机制中起主要作用。从头发现了几个候选标记物，其中之一是TGFbeta。我们可以证明，用血管紧张素转换酶抑制剂氯沙坦阻断小鼠的血管生长因子β途径，可以使主动脉壁结构正常化。我们最近证明，在小鼠模型中，循环中的TGFβ水平显著高于野生型小鼠。此外，给予氯沙坦可降低循环中的转化生长因子β水平。最近发表的在儿科人群的标准治疗中加入氯沙坦的结果显示，主动脉生长率显著降低。约翰霍普金斯大学是GenTAC登记的一部分，该登记登记了来自广泛遗传性疾病的主动脉瘤患者。最近，我们获得许可分析登记在册的首批207名MFS患者的TGFβ水平，并可能显示出与对照患者相比非常显著的增加。在目前的提案中，我们将(目标1)继续我们在MFS小鼠模型中的发现工作，并使用免疫分析和MRM来验证我们的候选标记物在小鼠和GenTAC群体中的有效性，MRM是一项基于质谱学的突破性技术，允许进行抗体非依赖性定量。在第二步(目标2)中，我们建立了小鼠急性主动脉夹层模型。这将使我们能够将从头发现扩大到急性环境，并弥合在急性夹层患者中发现生物标记物的差距。我们将使用免疫分析和MRM来验证我们的候选标记物，从而进一步了解主动脉夹层的预后。由于TGFbeta家族已被证明在MFS的发展中起着关键作用，我们的目标是建立一种能够在有限数量的样本中同时检测TGFbeta-1、-2和-3的多重检测方法(Aim 3)。我们最近获得了测量唾液中转化生长因子β的能力。这可能是一个有吸引力的选择，可以“筛查”患者的动脉瘤活动，并为个别患者的治疗提供指导。由于结缔组织疾病患者的主动脉疾病的许多方面，包括诊断程序和治疗措施，与那些没有综合征背景的患者相似，来自当前项目的见解将有助于对整个主动脉疾病患者的护理。约翰霍普金斯大学的机构每年在马里兰州直接创造约100亿美元的经济活动，比2002年的70亿美元增加了43%，相当于今天该州经济每24美元中就有1美元。2008年，约翰霍普金斯大学提供了4.5万个工作岗位，自2002年以来，每年创造700个新工作岗位。约翰霍普金斯大学的机构直接和间接地支持了马里兰州10万多个工作岗位，该州每29个工作岗位中就有一个。仅在巴尔的摩市，约翰斯·霍普金斯就直接和间接支持了60,000个工作岗位，占整个城市就业人数的16.7%。 公共卫生相关性：在工业化国家，急性夹层和主动脉瘤破裂占所有死亡人数的1-2%。临床上迫切需要找到这样的机制：(I)使我们能够在已知的主动脉瘤患者中识别有夹层的患者；(Ii)便于诊断有急性胸痛的患者的主动脉夹层；(Iii)帮助我们个体化治疗。目前的提案将在主动脉瘤和夹层的高级动物模型中使用蛋白质组学技术，以深入了解这些机制，并在大量主动脉疾病患者中验证发现。

项目成果

Unraveling the complexity of circulating forms of brain natriuretic peptide.

• DOI: 10.1373/clinchem.2007.086611
• 发表时间: 2007-07
• 期刊: Clinical chemistry
• 影响因子: 9.3
• 作者: Rebekah L. Gundry;J. V. Van Eyk

Milk fat globule protein epidermal growth factor-8: a pivotal relay element within the angiotensin II and monocyte chemoattractant protein-1 signaling cascade mediating vascular smooth muscle cells invasion.

牛奶脂肪球蛋白表皮生长因子-8：血管紧张素II和单核细胞趋化剂蛋白-1信号传导级联血管平滑肌细胞侵入的关键继电器元件。

• DOI: 10.1161/circresaha.108.187088
• 发表时间: 2009-06-19
• 期刊: Circulation research
• 影响因子: 20.1
• 作者: Fu Z;Wang M;Gucek M;Zhang J;Wu J;Jiang L;Monticone RE;Khazan B;Telljohann R;Mattison J;Sheng S;Cole RN;Spinetti G;Pintus G;Liu L;Kolodgie FD;Virmani R;Spurgeon H;Ingram DK;Everett AD;Lakatta EG;Van Eyk JE
• 通讯作者: Van Eyk JE

Recent advances in understanding Marfan syndrome: Should we now treat surgical patients with losartan?

• DOI: 10.1016/j.jtcvs.2007.08.047
• 发表时间: 2008-02-01
• 期刊: JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY
• 影响因子: 6
• 作者: Matt, Peter;Habashi, Jennifer;Dietz, Harry C.
• 通讯作者: Dietz, Harry C.