Molecular Pathways of Heart K Channel Regulation

超出规定的空间。长期目标是揭示在妊娠期功能性肥厚和产后恢复过程中参与心脏电和分子重塑的细胞和分子机制；特别是那些与K*通道表达式/函数相关的。/toK决定了啮齿动物和人类的心脏动作电位持续时间。在肥厚性心脏衰竭中，/to-f分子成分，特别是Kv4.3和Kv4.2通道下调，增加动作电位持续时间和心律失常发生。在怀孕期间，心律失常的风险增加，心脏功能肥厚，激素水平急剧变化；然而，目前还没有关于性激素诱导的K表达/功能变化的研究，这可能解释妊娠期间的心脏风险。Qpre，量化交货后的可逆性。因此，主要假设是，在怀孕和产后，性激素可能以基因组或非基因组方式调节Ito电流成分（例如kv1 .4, Kv4.2, Kv4.3, KChlP2, MiRP1, frequenin）。初步研究表明：a)妊娠期心脏Kv4.3、kv4和KCh/P2均降低，但Kv4.2通道/转录本及Kv4.3蛋白均未降低；b)与妊娠期一样，17-[3-estradio/(E2)]治疗降低了心脏Kv4.3和kv4 mRNA；c) E2降低cu/培养adu/t肌细胞中Kv4.3蛋白的表达；d) E2对电流有dua/效应，在100 nM（类似于人类妊娠）时，E2缩短了动作电位/，增加了动作电位/；而晚上10点E2则产生相反的效果；e) c-Src酪氨酸激酶被E2激活，从肥厚开始，Kv4.3的表达降低；f)酪氨酸激酶激活产生动作电位/促/长和/到电流还原。我们将主要使用小鼠和多种实验方法。具体目的是：1)调查在妊娠期和产后早期，动作电位的重塑，和/到快（/to-f）和/到慢（/to）。S)电流，以及潜在的分子成分。2)研究E2对ito .fllto.电流及其分子组分的作用，以及E2是否通过c-Src/MAPK（ERK）轴刺激Kv4.3基因转录。3)描述和定义Ito的非基因组调控机制。fand Kv4.3通道E2。4)研究c- src依赖性酪氨酸磷酸化对电流和Kv4亚型的短期和长期作用。5)确定Kv4.3中参与c-Src调控的motif。这些研究将为心肌肥厚早期K*通道重构的细胞和分子机制提供新的信息，并有助于设计新的预防医学策略。网站性能 ======================================== 节结束 ===========================================

EXCEEDTHE SPACE PROVIDED. The long term goal is to unravel cellular and molecular mechanisms involved in cardiac -electrical and molecular- remodeling during functional hypertrophy in pregnancy, and recovery in postpartum; in particular, those related to K* channel expression/function. /toK shapes the cardiac action potential duration in both rodents and humans. In failing hypertrophic hearts, /to-fmolecular components, in particular Kv4.3 and Kv4.2 channels are downregulated increasing action potential duration and arrhythmogenesis. During pregnancy, there is an increased risk of arrhythmias, the heart develops functional hypertrophy, and hormone levels dramatically change; however, no studies are available on chanqes in K expression/function induced by sex hormones, that may explain the cardiac risks durin.qpre,qnancyor their reversibility after delivery. Thus, the main hypothesis is that, during pregnancy and postpartum, sex hormones may regulate Ito current components (e.g. Kvl.4, Kv4.2, Kv4.3, KChlP2, MiRP1, frequenin) in a genomic or non-genomic fashion. Preliminary Studies show that: a) cardiac Kv4.3, Kvl.4 and KCh/P2, but not Kv4.2 channe/ transcripts, and Kv4.3 protein were reduced in/ate pregnancy; b) as in pregnancy, 17-[3-estradio/(E2) treatment reduced cardiac Kv4.3 and Kvl.4 mRNA; c) E2 reduced Kv4.3 protein expression in cu/tured adu/t myocytes; d) E2 had dua/ effects on/to currents, at 100 nM (similar to/ate human pregnancy), it shortened the action potentia/ and increased/to amp/itude; whereas, an opposite effect was produced by 10 pM E2; e) c-Src tyrosine kinase, which is activated by E2 and from the onset of hypertrophy, reduced expression of Kv4.3; and f) tyrosine kinase activation produced action potentia/ pro/ongation and/to current reduction. We will mainly use mice and multiple experimental approaches. The Specific Aims are to: 1) Investigate, during pregnancy and early post- partum, the remodeling of action potentials, and of/to fast (/to-f)and/to slow (/to.s)currents, and underlying molecular components. 2) Investigate the action of E2 on Ito.fllto.scurrents and their molecular components, and if E2 stimulates Kv4.3 gene transcription through the c-Src/MAPK(ERK) axis. 3) Characterize and define the mechanism(s) of non-genomic regulation of Ito.fand Kv4.3 channels by E2. 4) Investigate short- and long-term actions of c-Src-dependent tyrosine phosphorylation on/to currents and Kv4 isoforms. 5) Determine the motifs in Kv4.3 involved in its regulation by c-Src. These studies should provide new informationon the cellular and molecular mechanisms leading to the remodeling of cardiac K* channels inthe early stagesof hypertrophy,and help in the designof new strategiesfor preventiveMedicine. PERFORMANCE SITE ========================================Section End===========================================