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Excellence in Research: Involvement of MEF-2 transcription factor in mitochondrial stress response through SOD2

卓越研究：MEF-2 转录因子通过 SOD2 参与线粒体应激反应

基本信息

批准号：
1832026
负责人：
Atanu Duttaroy
金额：
$ 41.11万
依托单位：
Howard University
依托单位国家：
美国
项目类别：
Standard Grant
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-01 至 2022-08-31
项目状态：
已结题

来源：
https://www.nsf.gov/awardsearch/showAward?AWD_ID=1832026&HistoricalAwards=false
关键词：
Excellence Research Involvement MEF transcription

项目摘要

Oxygen, in combination with other molecules, generates energy that powers many biochemical processes. Without oxygen, humans could not exist. However, in the process of generating energy by "burning" nutrients with oxygen, certain "rogue" oxygen molecules, known as reactive oxygen species (ROS), are created as inevitable byproducts. One of the body's most powerful natural antioxidant enzymes is superoxide dismutase (SOD), which is responsible for disarming the most dangerous free radicals of all: the highly reactive superoxide radicals. All human cells produce superoxide dismutase to neutralize these superoxide radicals. It has been shown consistently that muscle activity leads to a strong increase in ROS production due to increased oxygen consumption. The investigator will test the hypothesis that a muscle specific protein, called Myocyte Enhancing Factor-2 (MEF-2), regulates SOD expression in the muscle tissue. Using a variety of molecular and cell biological procedures, the mechanistic link between MEF2 and SOD in muscle tissue will be evaluated. The project will provide state of the art technical skills to many undergraduate students who will be involved in many parts of the experiments. Howard University, a culturally diverse, research-intensive Historically Black College and University (HBCU) has approximately 97% of enrollees who are African Americans, therefore, the project will provide rich training opportunities for underrepresented minorities. Muscle function depends on high-level oxygen consumption and the concomitant high-level flux of toxic reactive oxygen species (ROS) that are generated as by-products of oxygen metabolism. Manganese superoxide dismutase (or SOD2) is engaged in the mitochondrial defense against reactive oxygen species (ROS). Loss of SOD2 function causes neonatal lethality. SOD2 function is more critical in muscles than in other tissues, which is consistent with the high level of oxygen consumption and prolific ROS generation by muscle mitochondria. So, unfettered ROS production is a mitochondrial hazard. As a transcription factor, Myocyte Enhancing Factor-2 (MEF-2) plays a critical role in the specification and subsequent differentiation of all muscle types. MEF-2 continues to be expressed in adult muscles with no other function attributed to MEF-2 in adult insects. In Drosophila, SOD2 expression is dependent on the presence of MEF-2 transcription factor. The central hypothesis of this proposal is that MEF-2 plays a novel, continuing role in adult muscle physiology by modulating mitochondrial stress response through SOD2. The three specific objectives are to determine: 1) the mechanistic connection between MEF-2 and SOD2 in adult muscle, 2) the influence of the MEF-2/SOD2 interaction on oxidative stress response and mitochondrial integrity, and 3) the broad biological significance of the MEF-2/SOD2 interaction on muscle biology at the whole organism level. The proposed study will contribute to the understanding of oxidative damage in muscle specifically in context to the biology of mitochondria. Research training opportunities will be provided to many underrepresented minority undergraduate and graduate students, who will acquire new skills with basic and translational applications.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

氧与其他分子结合，产生能量，为许多生物化学过程提供动力。没有氧气，人类就无法生存。然而，在通过氧气“燃烧”营养物质产生能量的过程中，某些“流氓”氧分子，即活性氧（ROS），作为不可避免的副产品产生。人体最强大的天然抗氧化酶之一是超氧化物歧化酶（SOD），它负责解除所有自由基中最危险的自由基：高度活性的超氧化物自由基。所有人类细胞都会产生超氧化物歧化酶来中和这些超氧化物自由基。研究一致表明，由于耗氧量增加，肌肉活动会导致活性氧产生的强烈增加。研究人员将测试一种肌肉特异性蛋白质，称为肌细胞增强因子-2 (MEF-2)，调节肌肉组织中SOD的表达的假设。使用各种分子和细胞生物学程序，MEF2和肌肉组织中SOD之间的机制联系将被评估。该项目将为许多参与实验的本科生提供最先进的技术技能。霍华德大学是一所文化多元化、研究密集型的历史黑人学院和大学（HBCU），大约97%的学生是非洲裔美国人，因此，该项目将为代表性不足的少数民族提供丰富的培训机会。肌肉功能依赖于高水平的氧气消耗和伴随的高水平的有毒活性氧（ROS），这些活性氧是氧气代谢的副产物。锰超氧化物歧化酶（SOD2）参与线粒体对活性氧（ROS）的防御。SOD2功能丧失可导致新生儿死亡。SOD2的功能在肌肉中比在其他组织中更重要，这与肌肉线粒体的高氧消耗和大量ROS生成是一致的。因此，不受限制的活性氧产生是线粒体危害。肌细胞增强因子-2 （Myocyte enhanced factor -2, MEF-2）作为一种转录因子，在所有肌肉类型的形成和分化过程中起着至关重要的作用。MEF-2在成虫肌肉中继续表达，而在成虫肌肉中没有其他功能。在果蝇中，SOD2的表达依赖于MEF-2转录因子的存在。该提案的中心假设是MEF-2通过SOD2调节线粒体应激反应，在成人肌肉生理中起着新的、持续的作用。三个具体目标是确定：1)MEF-2和SOD2在成人肌肉中的机制联系，2)MEF-2/SOD2相互作用对氧化应激反应和线粒体完整性的影响，以及3)MEF-2/SOD2相互作用在整个机体水平上对肌肉生物学的广泛生物学意义。提出的研究将有助于理解肌肉氧化损伤，特别是在线粒体生物学背景下。研究训练机会将提供给许多未被充分代表的少数民族本科生和研究生，他们将获得具有基本和转化应用的新技能。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。