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Department of Surgery

Jeffrey A. Jones, PhD Research

Jeffrey A. Jones, PhD

The formation of thoracic aortic aneurysms (TAA) 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. TAAs have numerous etiologies and recent data suggests that dissimilarities exist between TAA subtypes, specifically in regard to the proteolytic balance within the aortic wall. This is most notable for the matrix metalloproteinases. While the role of enhanced ECM proteolysis in TAA formation remains undisputed, the fundamental signaling mechanisms regulating the perturbations in matrix deposition and degradation in the developing aneurysm are not well understood.

Aneurysms afflict men two-to-four times more frequently than women. The risk demographics for developing an aneurysm are common to those of heart disease, and include atherosclerosis, hypertension, smoking, advanced age, and family history. With heart disease as the number one cause of death in America, and with the state of South Carolina having a higher than national average rate of cardiovascular disease-related death, there is heightened concern for aneurysm development. Thus, elucidating mechanisms driving aneurysm formation and progression may assist in developing strategies to arrest or even reverse aortic dilatation, carrying significant diagnostic, prognostic, and therapeutic implications for patient suffering from this insidious disease.

My research investigates mechanisms of thoracic aortic aneurysm (TAA) development related to aberrant TGF-b signaling and fibroblast transdifferentiation. Evidence from my laboratory and others, has implicated altered TGF-b signaling in TAA development. Examination of the TGF-β signaling pathway in an established murine model of TAA revealed alterations in TGF-β receptor abundance, shifting the signaling from a TGF-βRI to an ALK-1-mediated response that was coincident with TAA expansion. Importantly, recent data have suggested that this shift in TGF-b signaling through the ALK-1 pathway may result in the increased production of specific matrix metalloproteinases (MMPs) that contribute to the aberrant vascular remodeling occurring during TAA development.

Our current focus will extend these results and will determine how increased MMP production mediates the release of TGF-b that is sequestered in the extracellular matrix, and this mechanism feeds forward to drive fibroblast transdifferentiation. Using specific reagents designed to inhibit MT1-MMP activity and TGF-b signaling, as well as a conditional fibroblast-specific tamoxifen-inducible Cre-recombinase mouse, we will determine the cause-effect relationships between MT1-MMP activity, TGF-b signaling, myofibroblast transdifferentiation, and TAA formation and progression. The outcomes will provide exceptional insight into the development of TAA and may identify a cell-type and a significant signaling pathway through which TAA formation and progression can be attenuated. 


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Recent Publications:

  • Jones JA, Stroud RE, Kaplan BS, Leone AM, Bavaria JE, Gorman JH 3rd, Gorman RC, Ikonomidis JS. Differential protein kinase C isoform abundance in ascending aortic aneurysms from patients with bicuspid versus tricuspid aortic valves. Circulation. 2007 Sep 11;116(11 Suppl):I144-9.
  • Jones JA, Barbour JR, Stroud RE, Bouges S, Stephens SL, Spinale FG, Ikonomidis JS. Altered Transforming Growth Factor-Beta Signaling in a Murine Model of Thoracic Aortic Aneurysm. J Vasc Res. 2008 Apr 23;45(6):457-468.
  • Jones JA, Spinale FG, Ikonomidis JS. Transforming Growth Factor-beta Signaling in Thoracic Aortic Aneurysm Development: A Paradox in Pathogenesis. J Vasc Res. 2008 Sep 2;46(2):119-137.

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