ION CHANNEL DETERMINANTS OF MAST CELL ACTION IN THE HEART

心脏肥大细胞作用的离子通道决定因素

• 批准号: 8360591
• 负责人: Alexander James Stokes
• 金额: $ 27.51万
• 依托单位: UNIVERSITY OF HAWAII AT MANOA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-06-01 至 2012-09-23
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8360591
• 关键词: Affect; American; Calcium; Calcium Channel; Cannabinoids; Cardiac; Cardiomyopathies; Cardiotoxicity; Cardiovascular Diseases; Cardiovascular system; Cells; Centers of Research Excellence; Cessation of life; Chemicals; Funding; Grant; Heart; Heart Hypertrophy; Heart failure; Hypertrophy; Ion Channel; Knock-out; Knockout Mice; Medical; Medical Economics; Modeling; National Center for Research Resources; Pathology; Pharmaceutical Preparations; Principal Investigator; Reagent; Research; Research Infrastructure; Resources; Signal Transduction; Source; TRPV1 gene; United States National Institutes of Health; cannabinoid receptor; cost; economic impact; mast cell; new therapeutic target; research study; response

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.

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 8100万美国人受到至少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，并花费400亿美元的医疗费用。心脏病令人震惊的医学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，我们将研究两个钙通道的背景下，心脏肥大和中毒性心肌病。第一种是离子型大麻素受体TRPV1，它是响应大麻素和物理化学信号的钙进入的关键决定因素。第二个是CRACM 1，一种钙释放激活的钙通道，它允许钙在细胞内储存耗尽后进入细胞。 我们的中心假设是TRPV1和CRACM1的敲除和抑制可以保护心脏免于肥大并减轻药物诱导的毒性心脏病。拟议研究的总体目标是确定可能保护心脏免于i）肥大和ii）心脏毒性的试剂。拟议的实验利用Trpv1和Cracm1基因敲除小鼠和现有的TRPV1拮抗剂，在心脏肥大和毒性心脏病模型中，以确定TRPV1和CRACM1激活在这些病理中的作用。