The Jak/Stat Pathway and Mitochondrial Function

Jak/Stat 通路和线粒体功能

• 批准号: 8835118
• 负责人: ANDREW Charles LARNER
• 金额: $ 28.41万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-01 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8835118
• 关键词: Acute; Affect; Alanine; Apoptosis; Aspartic Acid; Cardiac; Cardiac Myocytes; Cell Nucleus; Cell Respiration; Cells; Chronic; Complex; Cytochromes; DNA Binding; DNA Binding Domain; Data; Development; Electron Transport; Gene Expression; Genetic Transcription; Goals; Health; Heart; Heart Diseases; Heart Injuries; Heart Mitochondria; Homeostasis; Human; Immune response; In Vitro; Inflammation; Injury; Ischemia; Laboratories; Location; Measures; Mediating; Mitochondria; Modeling; Morbidity - disease rate; Mus; Mutate; Mutation; Myocardial Infarction; Myocardial Ischemia; Myocardial dysfunction; NADH dehydrogenase (ubiquinone); Nuclear; Nuclear RNA; Organ; Oxidative Phosphorylation; Pathogenesis; Pathology; Pathway interactions; Phosphorylation; Physiological; Physiology; Play; Production; Proteins; Publishing; Reactive Oxygen Species; Regulation; Respiration; Role; STAT protein; STAT1 gene; STAT3 gene; Serine; Signal Transduction; Stress; Testing; Time; Tissues; Transgenes; Transgenic Animals; Transgenic Mice; Transgenic Organisms; Tyrosine; United States; Wild Type Mouse; cell growth; cell transformation; cytokine; defined contribution; heart function; in vivo; injured; mortality; novel; overexpression; prevent; protective effect; research study; response; selective expression; transcription factor

DESCRIPTION (provided by applicant): The Stat transcription factors play pivotal roles in controlling the expression of genes involved in immune responses, cell transformation and maintaining homeostasis. Published results from this lab demonstrate that there is a pool of Stat3 that is localized in the mitochondria (mitoStat3) where it functions to control cellular respiration both in cells and in cardiac tissue. Preliminary results with a transgenic mice that express Stat3 that is targeted heart mitochondria indicate that it the transgenic protein protects hearts from ischemia induced decreases in the activity of complex I of the electron transport chain, production of reactive oxygen species (ROS) from mitochondria and release of cytochrome C from the mitochondria. Preliminary results in this proposal also define a new function of Stat1 as a repressor of mitochondrial gene expression. In addition, Stat1 represses the transcription of nuclear RNAs that encode components of the electron transport chain. It appears that the actions of Stat1 might antagonize the effects of Stat3 in regulation of mitochondrial homeostasis as well as their well knows opposing actions on cell growth and inflammation. Experiments are proposed to define the contribution of mitoStat3 to the cardio-protective effects of this transcription factor in acute and chronic models of heart injury. Since the mechanisms by which Stat1 represses mitochondrial transcription leading to decreased mitochondria function appear to oppose the effects of mitoStat3, we will examine if mitochondrial targeted Stat3 transgenes show enhanced protection in a Stat1-/- background. Completion of these studies will elucidate a mitochondria-nuclear signaling network that is regulated by Stat3's location in the both the nucleus and mitochondria.

描述（由申请人提供）：Stat转录因子在控制参与免疫应答、细胞转化和维持稳态的基因表达中起关键作用。该实验室发表的结果表明，有一个位于线粒体（mitoStat 3）中的Stat 3库，它的功能是控制细胞和心脏组织中的细胞呼吸。表达Stat 3的转基因小鼠的初步结果表明，Stat 3是靶向心脏线粒体，其转基因蛋白保护心脏免受缺血诱导的电子传递链复合物I活性降低、线粒体产生活性氧（ROS）和线粒体释放细胞色素C。该提案的初步结果还定义了Stat 1作为线粒体基因表达阻遏物的新功能。此外，Stat 1抑制编码电子传递链组分的核RNA的转录。Stat 1的作用似乎可以拮抗Stat 3在调节线粒体稳态中的作用，以及它们对细胞生长和炎症的众所周知的相反作用。 提出实验来定义mitoStat 3对该转录因子在急性和慢性心脏损伤模型中的心脏保护作用的贡献。由于Stat 1抑制线粒体转录导致线粒体功能降低的机制似乎与mitoStat 3的作用相反，我们将研究线粒体靶向Stat 3转基因是否在Stat 1-/-背景下显示出增强的保护作用。这些研究的完成将阐明一个由Stat 3在细胞核和线粒体中的位置调节的细胞核信号网络。

项目成果

The role of Tyk2 in regulation of breast cancer growth.

• DOI: 10.1089/jir.2011.0023
• 发表时间: 2011-09
• 期刊: Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research
• 作者: Qifang Zhang;J. Sturgill;M. Kmieciak;Karol Szczepanek;Marta Derecka;Catherine M. Koebel;L. Graham;Yun Dai;Shuang Chen;S. Grant;J. Cichy;K. Shimoda;A. Gamero;M. Manjili;H. Bear;D. Conrad;A. Larner

Toward a new STATe: the role of STATs in mitochondrial function.

• DOI: 10.1016/j.smim.2013.12.005
• 发表时间: 2014-02
• 期刊: Seminars in immunology
• 影响因子: 7.8
• 作者: Meier JA;Larner AC
• 通讯作者: Larner AC