The goal of this proposal is to synthesize the Candidate's expertise in cell and tissue mechanics with the molecular mechanisms of TGF-(31 activity and cardiovascular pathophysiology to appropriately examine aortic valve (AV) sclerosis. The Candidate will be mentored by Dr. Joanne E. Murphy-Ullrich, an expert in molecular mechanisms of TGF-01 activation and activity, and co-mentored by Dr. Louis J. Dell'ltalia, an expert in cardiovascular physiology, valvular disease, and left ventricle remodeling. Training during this award includes didactic course work, rotations in the laboratories of the mentor and co-mentor, and regular meetings, seminars, and journal clubs. This mentored training is essential for the Candidate to investigate the proposed research and develop future NIH funding proposals in biomedical research. Recently, we found that aortic valve (AV) leaflets exposed to both cyclic strain and bioactive TGF-01 resulted in a synergistic phenotypic shift of aortic valve interstitial cells (AVICs) to myofibroblasts with increased collagen production and 11-fold increase in total (latent + bioactive) TGF-P1 expression compared to either stimulus alone, suggesting positive interactions between AVIC strain and TGF-01 signaling (Merryman, Cardiovascular Pathology, 2007). However, the mechanisms by which mechanical strain regulate TGF-01 activity in the AV are unknown. We propose that the natural progression of AV sclerosis is due to altered mechano-dependent signaling of TGF-(31 by AVICs subjected to increased cellular deformation. Thus, we hypothesize that regulation of TGF-31 synthesis and/or bioactivation is dependent on cellular strain, leading to phenotypic changes of the AVICs, altered ECM, and AV sclerosis. We will test this hypothesis with the following aims:
Specific Aim 1 - Quantify the dependence of TGF-01 synthesis and bioactivation on physiologic and pathophysiologic strain environments in monolayer culture of AVICs.
Specific Aim 2 - Quantify TGF-p1 synthesis and bioactivation from AVICs under physiologic and pathophysiologic strains in situ.
The proposal seeks to elucidate the mechano-dependent molecular mechanisms of TGF-|31 and it'srole in aortic valve disease. As valve disease prevalence grows with age, and due to our increasing lifespan, understanding these mechanisms and how they may be prevented are very important.
|Chen, Joseph; Peacock, Jon R; Branch, Janelle et al. (2015) Biophysical analysis of dystrophic and osteogenic models of valvular calcification. J Biomech Eng 137:020903|
|Chen, Joseph; Ryzhova, Larisa M; Sewell-Loftin, M K et al. (2015) Notch1 Mutation Leads to Valvular Calcification Through Enhanced Myofibroblast Mechanotransduction. Arterioscler Thromb Vasc Biol 35:1597-605|
|Bowler, Meghan A; Merryman, W David (2015) In vitro models of aortic valve calcification: solidifying a system. Cardiovasc Pathol 24:1-10|
|Sewell-Loftin, Mary Kathryn; DeLaughter, Daniel M; Peacock, Jon R et al. (2014) Myocardial contraction and hyaluronic acid mechanotransduction in epithelial-to-mesenchymal transformation of endocardial cells. Biomaterials 35:2809-15|
|West, James D; Austin, Eric D; Gaskill, Christa et al. (2014) Identification of a common Wnt-associated genetic signature across multiple cell types in pulmonary arterial hypertension. Am J Physiol Cell Physiol 307:C415-30|
|Fisher, Charles I; Chen, Joseph; Merryman, W David (2013) Calcific nodule morphogenesis by heart valve interstitial cells is strain dependent. Biomech Model Mechanobiol 12:5-17|
|Hutcheson, Joshua D; Chen, Joseph; Sewell-Loftin, M K et al. (2013) Cadherin-11 regulates cell-cell tension necessary for calcific nodule formation by valvular myofibroblasts. Arterioscler Thromb Vasc Biol 33:114-20|
|Merryman, W David; Schoen, Frederick J (2013) Mechanisms of calcification in aortic valve disease: role of mechanokinetics and mechanodynamics. Curr Cardiol Rep 15:355|
|Hutcheson, Joshua D; Ryzhova, Larisa M; Setola, Vincent et al. (2012) 5-HT(2B) antagonism arrests non-canonical TGF-?1-induced valvular myofibroblast differentiation. J Mol Cell Cardiol 53:707-14|
|Hutcheson, Joshua D; Venkataraman, Raghav; Baudenbacher, Franz J et al. (2012) Intracellular Ca(2+) accumulation is strain-dependent and correlates with apoptosis in aortic valve fibroblasts. J Biomech 45:888-94|
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