ION CHANNEL DETERMINANTS OF MAST CELL ACTION IN THE HEART

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 8100万美国人至少受到一种心血管疾病的影响。2010年，心力衰竭将导致八分之一的死亡，并造成400亿美元的医疗费用。心脏病理学令人震惊的医疗和经济影响为寻找和研究新的治疗靶点创造了令人信服的理由。 在这里，我们将研究心肌肥厚和中毒性心肌病背景下的两种钙通道。第一个是离子型大麻素受体TRPV1，它是钙离子进入的关键决定因素，对大麻素和物理化学信号都有反应。第二个是CRACM1，一种钙释放激活的钙通道，它允许钙在细胞内存储耗尽后进入细胞。 我们的中心假设是，敲除和抑制TRPV1和CRACM1可以保护心脏免受肥厚的影响，并减轻药物引起的中毒性心脏病。这项拟议研究的总体目标是确定可能保护心脏免受i)肥大和ii)心脏毒性影响的试剂。建议的实验利用TRPV1和CRACM1基因敲除小鼠，以及现有的TRPV1拮抗剂，在心肌肥大和中毒性心脏病的模型中，确定TRPV1和CRACM1激活在这些病理中的作用。

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.