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: 7815944
• 负责人: Harry C., III Dietz
• 金额: $ 50万
• 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 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7815944
• 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）：此申请解决广泛的挑战领域（06）“启用技术”和特定的变更主题，06- HL-101“开发技术，用于评估容易破裂或解剖的主动脉动脉瘤”。主动脉夹层描述了体内主血管壁的撕裂。潜在的病理是多种多样的，诱发因素包括主动脉瘤和结缔组织的疾病。这是一个威胁生命的事件，尤其是如果解剖位于胸主动脉的上升部分，因为它可能通过损害主动脉瓣和血液流过冠状动脉动脉而导致全球心肌缺血。主动脉的破裂更为罕见，但几乎总是与100％死亡率有关。在目前的提案中，我们解决了临床上相关和紧迫的需求，以阐明（i）将使我们能够确定已知主动脉瘤患者（ii）患者在患有急性胸痛患者主动脉夹层的患者中识别出诊断为剖析的患者，急性胸痛和（III）有助于使用个体化治疗。主动脉扩张是由多种机制引起的，包括遗传结缔组织疾病，例如Marfan综合征（MFS）。我们将在当前建议中使用MFS作为主动脉疾病的模型，因为我们已经表明，对这种疾病的全面理解提供了对血管壁生物学的更多了解，并确定了与主动脉动脉瘤和剖记有关的途径。在2006年，我们表明过度TGFBETA信号传导在MFS小鼠模型中MFS的发病机理中起主要作用。从头发现已经确定了一些候选标记，其中一个是TGFBETA。我们可以证明，用AT1-ANATGONIST LOSARTAN阻止鼠标中的TGFBETA途径，将主动脉壁架构归一化。我们最近证明，小鼠模型中的循环TGFBETA水平明显高于野生型小鼠。此外，通过洛萨坦的给药，循环TGFBETA的水平降低。最近发表的小儿种群中将氯沙坦添加到标准疗法中的结果表明，主动脉生长率显着降低。约翰·霍普金斯（Johns Hopkins）是GENTAC注册中心的一部分，该注册表从各种可遗传的疾病中招募患有主动脉动脉瘤的患者。最近，我们获得了分析TGFBETA水平注册中的前207名MFS患者的许可，与对照患者相比，TGFBETA水平的注册表可能会显示出高度显着的增加。在当前的提案中，我们将（AIM 1）继续在MFS的小鼠模型中进行发现工作，并使用免疫测定和MRM验证小鼠中的候选标记，以及基于质谱的突破性技术，允许抗体与抗体无关定量。在第二步（AIM 2）中，我们在小鼠中建立了急性主动脉夹层模型。这将使我们能够扩大从头发现的急性环境，并弥合急性解剖患者的生物标志物发现的差距。我们将使用免疫测定和MRM验证候选标记，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，因此我们旨在开发多重测定（AIM 3），能够同时在有限的样本中同时测量TGFBETA -1，-2和-3。我们最近获得了测量唾液中TGFBETA的能力。这可能是“筛查”患者进行动脉瘤活动的有吸引力的选择，并为单个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（包括诊断程序和治疗措施）的许多方面与具有非混合性背景的患者相似，因此当前项目的见解将有助于总体主动脉疾病患者的护理。每年约翰·霍普金斯机构在马里兰州直接产生约100亿美元的经济活动，比2002年产生的70亿美元增长了43％，相当于当今该州经济中的每二十四美元之一。 2008年，约翰·霍普金斯（Johns Hopkins）机构提供了45,000个工作岗位，并自2002年以来每年创造了700个新工作。仅在巴尔的摩市，约翰·霍普金斯（John Hopkins）就直接和间接地支持60,000个工作岗位，占城市就业的16.7％。 公共卫生相关性：主动脉瘤的急性解剖和破裂，占工业化国家所有死亡人数的1-2％。临床需求迫切需要找到（i）使我们能够识别出已知主动脉瘤性障碍性瘤患者的患者（II）促进急性胸痛患者的主动脉夹层的诊断和（iii）帮助我们个性化治疗。当前的建议将在主动脉瘤和解剖的晚期动物模型中使用蛋白质组学技术，以深入了解这些机制，并验证大量主动脉疾病患者的发现。