Intracellular Signaling in Thoracic Aortic Aneurysms

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DESCRIPTION (provided by applicant): The formation of ascending thoracic aortic aneurysms (ATAA) is a multifactorial process influenced by both cellular and extracellular mechanisms. These mechanisms lead to alterations in the vascular environment through remodeling of the extracellular matrix (ECM); an invariant feature directly implicated in aortic dilatation and aneurysm development. ATAAs have numerous etiologies. Recent data suggests that dissimilarities exist between these ATAA subtypes with regard to the proteolytic balance within the aortic wall, most notably for the matrix metalloproteinases (MMPs). However, the profiles of the upstream signaling mediators regulating these differences remain unknown. Intracellular signaling events within the aortic vascular wall result in dynamic changes in the production and secretion of extracellular matrix protein components, including the modifying enzymes that drive the remodeling process. Of these, the tumor necrosis factor-1 (TNF-1) and transforming growth factor-2 (TGF-2) signaling families are implicated in protease activation and ECM remodeling. Furthermore, critical cellular intermediates like protein kinase C (PKC) and nuclear factor :B (NF:B) may function as integrators of these and other intracellular signaling pathways which are operative during ATAA development. Therefore, using a large unique bank of resected human aortic tissue specimens (n=274), obtained from multiple institutions, the primary objectives of this project proposal are designed to generate proof of principle that the activation of key intracellular signaling pathways is a fundamental prerequisite for the induction of aberrant vascular remodeling and the consequent development of ATAA. This will be accomplished by measuring relative mRNA expression levels of key signaling intermediates in a subset of ATAA specimens using pathway-focused PCR array technology. These studies will identify genes that are chronically altered in expression, in two key signal transduction pathways (TGF-2, TNF-1), and surrounding two key signaling intermediates (PKC, NF:B). Then using quantitative immunoblotting techniques, relative protein amounts of the genes with elevated expression, from the PCR array analysis, will be determined in the full bank of human ATAA specimens and controls (n=274). Together, these studies will determine chronically elevated signaling molecules that are likely to be operative during ATAA development. These data will formulate the basis for subsequent R01 grant submissions centered on hypothesis-driven studies aimed at elucidating the functional role of these signaling pathways/molecules in ATAA development. By advancing our understanding of the signaling events contributing to ATAA formation and progression, identification of therapeutic targets within these key signaling pathways could result in novel diagnostic and therapeutic strategies. PUBLIC HEALTH RELEVANCE Thoracic aortic aneurysm disease is a devastating disease process which often results in death because of a lack of aneurysm specific symptomology. There are currently no effective, non-surgical clinical treatment protocols available to treat thoracic aneurysm disease. The present proposal defines studies that will identify chronically elevated signaling molecules which may serve as aneurysm-specific targets for the development of novel diagnostic and therapeutic strategies.