Mitochondrial K+ Channels and Cardioprotection

描述（由申请人提供）：我们研究项目的总体目标是阐明内源性和其他机制对缺血再灌注（IR）损伤的保护，并利用这些知识开发新的治疗IR疾病的方法，如心脏病发作和中风。许多心脏保护策略似乎集中在线粒体钾通道上，作为保护信号的必要和充分的效应器。然而，这些渠道的身份和监管仍然存在争议。到目前为止，我们已发表的研究以及本文中包含的令人兴奋的初步数据，将我们的重点放在了一种新的线粒体K+通道上，该通道是保护所必需的，以前没有涉及保护性信号。值得注意的是，缺乏这个通道似乎会产生代谢表型。我们还发现了一类新的内源性信道调制器。在本提案中，Aim 1将描述通道及其在心脏保护中的作用，Aim 2将研究通道之间的联系

DESCRIPTION (provided by applicant): The overall goal of our research program is to elucidate endogenous and other mechanisms of protection against ischemia-reperfusion (IR) injury, and to exploit this knowledge to develop new therapies for IR disease conditions such as heart attack and stroke. Many cardioprotective strategies appear to converge on mitochondrial potassium channels as necessary and sufficient effectors of protective signaling. However, the identity and regulation of these channels remains controversial. Our published research to date, and exciting preliminary data contained herein, have directed our focus to a novel mitochondrial K+ channel that is required for protection and has not previously been implicated in protective signaling. Notably, absence of this channel appears to yield a metabolic phenotype. We have also identified a novel class of endogenous channel modulators. In this proposal, Aim 1 will characterize the channel and its role in cardioprotection, Aim 2 will investigate links between the channel and cardiac metabolism, and Aim 3 will study its regulation by endogenous signals. We will use a variety of state-of-the -art techniques, including patch-clamp of mitoplasts (isolated mitochondrial inner membranes), and Seahorse XF methodology to assess cardiomyocyte bioenergetics. This dual-PI proposal draws on the expertise of both investigators (Brookes - mitochondrial biology, metabolic screening, cardiac patho-physiology; Nehrke - ion channels, mouse genetics, mitochondrial physiology). Our productive track-record (8 original research articles and 3 reviews funded by this project in 3 years) imparts a high probability that the completion of these 3 aims will yield critical information about this channel, which is a novel potential drug target for cardioprotection.