C-terminal Peptide of Cardiac Troponin I for the Treatment of Diastolic Hear Failure

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SUMMARY OF SUPPLEMENT RESEARCH Calcific aortic valve disease (CAVD) is a common and severe valvular disease that causes heart failure. Surgical valve replacement is currently the only available treatment. However, recent clinical data indicate that the pathological myocardial remodeling and failing continue after valve replacement, severely limiting the therapeutic effect on long-term survival. We have reported that knockout of the gene encoding calponin isoform 2 attenuates hyperchloremia-caused aortic valve calcification in ApoE knockout mice, suggesting a novel molecular target for the treatment and prevention of CAVD. Here we propose to expand the parent research project with new investigations into the role of calponin 2 in the pathogenesis and progression of CAVD and the underlying mechanisms for the development of non-surgical treatment and prevention. To further investigate the therapeutic effect of calponin 2 deletion or reduction on attenuating the pathogenesis and progression of CAVD and to understand the underlying molecular mechanism, we shall apply integrative multi-level approaches to pursue two supplement specific aims. Aim S1 is to characterize the longitudinal benefit of calponin 2 deletion and reduction for mitigating CAVD and the effectiveness in representative mouse models of different etiologies. The studies will investigate the states of disease in which calponin 2 reduction will effectively prevent attenuate or reverse the calcific lesion of aortic valve. Aim S2 is to understand the mechanoregulation of calponin 2 in calcific differentiation of aortic valvular interstitial cells. Aortic valve functions in a dynamic mechanical environment. Cellular mechanoregulation plays an important role in the pathogenesis of aortic valve calcification. Calponin 2 is a troponin-like cytoskeleton mechanoregulatory protein that is increased in calcified human aortic valves. Among the multiple cell types involved the pathogenesis of CAVD, we shall focus on the role of mechanoregulated functions of calponin 2 in aortic valve interstitial cells during trans-differentiation into myofibroblasts and osteogenic cells. The studies will learn mechanistic insights into the development of calponin 2-targeted treatment and prevention of CAVD in the context of valvular hemodynamics and pathological tissue remodeling. This supplement research is proposed on the basis of strong scientific premise and prior research, innovative molecular targets, testable hypothesis and multi-level integrative experimental systems. The anticipated results will have major scientific and medical implications. With demonstrated expertise in calponin research and in collaboration with CAVD expert, our productive team of investigators has all necessary technical capacities, methodology and tools, and mouse models to launch the new studies and make timely progresses to develop a more comprehensive research program toward translation into new non-surgical treatment and prevention of CAVD.