Transforming Growth Factor-beta Signaling Pathways in Thoracic Aortic Aneurysms

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DESCRIPTION (provided by applicant): Thoracic aortic aneurysm (TAA) disease is a potentially devastating disease process which often causes death by rupture in the absence of symptoms. TAA formation proceeds by a multifactorial process, influenced by both cellular and extracellular mechanisms that result in alterations of the structure and composition of the extracellular matrix (ECM). There are currently no effective non-surgical clinical treatment protocols available which will halt or reverse the aortic remodeling process during aneurysm formation. While current data demonstrate that this pathological remodeling is a result of a significant spatiotemporal change in the expression/abundance of the matrix metalloproteinases and their endogenous tissue inhibitors, little attention has been focused on the upstream signaling events that regulate the remodeling process. One upstream signaling protein known to alter the structure and composition of the ECM, and known to play an important role in vascular remodeling is transforming growth factor-beta (TGF-b). Examination of the TGF-b signaling pathway during TAA development revealed a shift in signaling from a TGF-bRI-mediated pathway to an ALK-1- mediated pathway. Accordingly, the present proposal will test the central hypothesis that signaling through the ALK-1 pathway drives aberrant vascular remodeling and TAA development. Using a small animal model of TAA, cellular studies of isolated aortic fibroblasts, and in vivo delivery of specific genes/inhibitors, this hypothesis will be tested by: (1) establishing the relationship between alterations in TGF-b signaling and changes in the determinants of ECM degradation/deposition during TAA development; (2) demonstrating that alterations in MMP/TIMP expression and abundance are mediated by the effects of TGF-b on aortic fibroblasts; and (3) demonstrating that MMP/TIMP abundance and aortic dilatation can be altered by modifying TGF-b signaling in vivo. This unique set of proposed studies will establish the relationship between altered TGF-b signaling and the production of the degradative determinants of ECM remodeling. The outcomes of this proposal will provide exceptional insight into the development of TAA and may identify significant targets through which TAA formation and progression can be disrupted.