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.
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.
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