Exploration of key proteases and validation of biomarkers in genetically triggered thoracic aortic aneurysms

点击翻译按钮获取中文摘要

PROJECT SUMMARY: Thoracic aortic aneurysms (TAAs) develop as a consequence to abnormal remodeling of the aortic extracellular matrix (ECM). This process weakens the aortic wall and leads to gross dilation that typically progresses to rupture in a generally asymptomatic way. There are several well described etiologies that contribute to the formation and progression of TAA. These include genetic syndromes, as well as, non-syndromic inheritable predispositions. Current treatment options are limited and consist of surgical reconstruction or endo- vascular intervention; neither of which address the underlying mechanisms responsible for disease. It is well described that TAAs are influenced by both intra- and extra- cellular mechanisms that function to regulate matrix deposition and degradation, in part, through activation of the matrix metalloproteinases (MMPs) and enhanced TGF-β signaling. Previously, this laboratory identified the membrane-bound type-1 MMP (MT1-MMP) as a key mediator of TAA formation through its role in both pericellular proteolysis by activation of MMP-2 and intracellular TGF-β signaling. Furthermore, we demonstrated that phosphorylation of MT1-MMP regulates enzymatic function by altering its cellular location, thus mediating access to specific substrates, shifting its role in ECM remodeling and overall progression of TAA. Despite advancements in our understanding of the pathobiology of TAA, these innovations have yet to be translated into development of screening, diagnosis, tracking, and treatment of TAA. Therefore, there is an urgent need to not only identify therapeutic targets, but also develop non-invasive methods for the early detection of TAA preceding life threatening aortic complications. Work from our laboratory and others have confirmed that specific MMPs, and their endogenous inhibitors (TIMPs) are implicated in the pathogenesis of TAA, and similar findings have been demonstrated with microRNAs. Preliminary data from our laboratory has established that theses MMPs, TIMPs, and microRNAs can be directly quantitated in plasma, and levels can be potentially utilized in an algorithm for screening patients for both the presence and etiological subtype of TAA. However, little is known in regards to circulating levels of these analytes in individuals with genetically triggered TAA. Importantly, the established comprehensive biospecimen repository of Genetically Triggered Aortic Aneu- rysms and Cardiovascular Conditions (GenTAC) is composed of aortic tissue and plasma specimens collected from individuals of multiple common predispositions linked to TAA. Therefore, we propose an investigation uti- lizing this resource to derive novel therapeutic and diagnostic strategies for different subtypes of TAA. Accord- ingly, the central hypotheses of this proposal are that the function of MT1-MMP is altered in different etiological subtypes of TAA, and these subtypes are distinguishable by a distinct plasma profile of MMPs, TIMPs, and microRNAs, which will be examined through the following specific aims: (1) Demonstrate a differential role of MT1-MMP in genetically triggered thoracic aortic aneurysms, and (2) Confirm a previously identified plasma biomarker panel for identification of TAA in patients with genetic predisposition.