This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Eighty-one million Americans are affected by at least one type of cardiovascular disease. In 2010 heart failure will contribute to 1 in 8 deaths and cost $40 billion in medical expenses. The staggering medical and economic impact of cardiac pathologies creates a compelling justification to find and study new therapeutic targets. Here we will study two calcium channels in the context of cardiac hypertrophy and toxic cardiomyopathy. The first is the ionotropic cannabinoid receptor, TRPV1, which is a critical determinant of calcium entry in response to both cannabinoids and physico-chemical signals. The second is CRACM1, a calcium release-activated calcium channel, which allows calcium entry into cells following depletion of the intracellular stores. Our central hypothesis is that knockout and inhibition of TRPV1 and CRACM1 can protect the heart from hypertrophy and alleviate drug induced toxic cardiopathies. The overall objective of the proposed research is to identify reagents that could potentially protect the heart from i) hypertrophy and ii) cardiotoxicity. The proposed experiments utilize Trpv1 and Cracm1 knockout mice, and existing TRPV1 antagonists, in a model of cardiac hypertrophy, and toxic cardiopathy, to identify the contribution of TRPV1 and CRACM1 activation in these pathologies.
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