Regulation of mitochondrial calcium signaling by Pannexin2

Pannexin2 对线粒体钙信号传导的调节

• 批准号: RGPIN-2016-05471
• 负责人: Naus, Christian
• 金额: $ 2.77万
• 依托单位: University of British Columbia
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2018
• 资助国家: 加拿大
• 起止时间: 2018-01-01 至 2019-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=660705
• 关键词: Regulation; mitochondrial; calcium; signaling; Pannexin2

** * 0* 0* 1* 242* 1382* 11* 3* 1621* 14.0* * * * * *** * Normal* 0* * * * * false* false* false* * EN-US* ZH-CN* X-NONE* * * * * * * * * * * * * * * * * * * * * * * * * ** * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * **** /* Style Definitions */*table.MsoNormalTable* {mso-style-name:"Table Normal";* mso-tstyle-rowband-size:0;* mso-tstyle-colband-size:0;* mso-style-noshow:yes;* mso-style-priority:99;* mso-style-parent:"";* mso-padding-alt:0cm 5.4pt 0cm 5.4pt;* mso-para-margin-top:0cm;* mso-para-margin-right:0cm;* mso-para-margin-bottom:10.0pt;* mso-para-margin-left:0cm;* text-align:justify;* text-justify:inter-ideograph;* text-indent:36.0pt;* mso-pagination:widow-orphan;* font-size:12.0pt;* font-family:"Times New Roman";* mso-ansi-language:EN-US;* mso-fareast-language:ZH-CN;}*******Pannexins are channel proteins that are*related to the connexin family of gap junction proteins. Unlike connexins, pannexins*do not from a link between two adjacent cells but connect directly to the external*environment of the cells. However, we recently showed that one member of the*pannexins, Panx2, is restricted to the interior of the cell. Most importantly,*it is closely associated with mitochondria, the energy powerhouse of the cell. Defects in mitochondria are implicated in*brain disorders including Alzheimer's and Parkinson's disease. Since pannexin*channels have been reported to be permeable to calcium ions, we hypothesize*that under normal conditions Panx2 channel activity regulate mitochondrial*energy production by regulating mitochondrial calcium levels. In contrast,*under pathological conditions, dysregulation of Panx2 channel activity triggers*mitochondrial calcium overload leading to cell death. We propose to test this*hypothesis in three interrelated aims. In Aim 1, we will examine whether*alteration of mitochondrial energy production will lead to changes in Panx2*expression and distribution. If an increase in Panx2 is related to*mitochondrial dysfunction, we will determine whether Panx2 modulates the*production of energy molecule ATP in Aim 2. After confirming the critical role*of Panx2 in mitochondrial signaling, we will investigate whether Panx2 activity*influences the level mitochondrial calcium in Aim 3. Findings from our proposal*will reveal novel strategies to curtail mitochondrial dysfunction and lay the*foundation of possible therapeutic interventions in brain diseases. *** *

* * * 0 * 0 * 1 * 242 * 1382 * 11 * 3 * 1621 * 14.0 * * * * * *** * 正常* 0 * * * * * 假*假*假* * en - us *应用* X-NONE * * * * * * * * * * * * * * * * * * * * * * * * * ** * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * ** * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * **** /* 样式定义* / *表。MsoNormalTable* {mso-style-name:"Table Normal"；* mso-tstyle-rowband-size: 0;* mso-tstyle-colband-size: 0;* mso-style-noshow:是的;* mso-style-priority: 99;* mso-style-parent:“”;* mso-padding-alt:0cm 5.4pt；* mso-para-margin-top: 0厘米;* mso-para-margin-right: 0厘米;* mso-para-margin-bottom: 10.0分;* mso-para-margin-left: 0厘米;* text-align:证明;* text-justify: inter-ideograph;* indent: 36.0分;* mso-pagination: widow-orphan;*字体大小:12.0分;* font-family：宋体；* mso-ansi-language: en - us;* mso-fareast-language:应用;*******Pannexins是与间隙连接蛋白的连接蛋白家族相关的通道蛋白。与连接蛋白不同，泛连接蛋白不是连接两个相邻细胞，而是直接连接到细胞的外部环境。然而，我们最近发现pannexins的一个成员Panx2被限制在细胞内部。最重要的是，它与细胞的能量发电站——线粒体密切相关。线粒体缺陷与阿尔茨海默病和帕金森病等脑部疾病有关。由于pannexin通道已被报道可渗透钙离子，我们假设在正常条件下，Panx2通道活性通过调节线粒体钙水平来调节线粒体能量的产生。相反，在病理条件下，Panx2通道活性失调会引发线粒体钙超载，导致细胞死亡。我们建议用三个相互关联的目标来检验这一假设。在Aim 1中，我们将检验线粒体能量产生的*改变是否会导致Panx2*表达和分布的变化。如果Panx2的增加与线粒体功能障碍有关，我们将确定Panx2是否调节Aim 2中能量分子ATP的产生。在确认Panx2在线粒体信号传导中的关键作用*后，我们将研究Panx2活性*是否影响Aim 3线粒体钙水平。我们的研究结果将揭示抑制线粒体功能障碍的新策略，并为可能的脑部疾病治疗干预奠定基础。* * * *