Translational Control of Growth and Apoptosis in C. Elegans Development by Initiation Factor Isoforms

通过起始因子异构体对线虫发育中生长和凋亡的转化控制

• 批准号: 0842475
• 负责人: Brett Keiper
• 金额: $ 52.55万
• 依托单位: East Carolina University
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=0842475&HistoricalAwards=false
• 关键词: Translational; Control; Growth; Apoptosis; C.

New gene expression is required for cells to begin to grow and divide (proliferation) or to alter their fate (differentiation). The development of egg and sperm (gametes) likewise involves crucial periods of gene expression and differentiation. Early cells divide and then differentiate into either sperm or oocytes. Gene transcription is active early in gametogenesis, but becomes silenced as cells enter meiosis, and thus mRNAs that have been stored during the proliferative phase become the sole means to produce new proteins. Developmentally important mRNAs become translated into protein on ribosomes in the oocyte, spermatocyte or embryo, and the new proteins direct either continued differentiation or cell death (apoptosis). This research project is focused on proteins called eIF4 factors, which contact the mRNAs to be translated as the first step in recruiting them to the protein synthesis machinery. Specifically, the activities of eIF4 factors that lead to new protein synthesis in gametes and embryos will be investigated. Animal model systems such as the soil-dwelling nematode worm, Caenorhabditis elegans, are essential in this research because they are generally simpler than human embryos. The C. elegans embryo develops from a fertilized egg to an organized multi-cellular embryo in a manner very similar to that of higher animals. Fortunately these worms have a far simpler body plan made up of just a few muscles, neurons, digestive and reproductive organs. More importantly in the present context, the critical genes required are very similar in this simple model system. Because protein synthesis mechanisms are well conserved in animals, research findings using C. elegans will shed light on gene expression in vertebrate gametes and embryos, where such methods are not feasible or practical.Broader Impact and Educational Benefit: This project directly impacts the education of a minority and a female graduate student who are completing Ph.D. thesis research in Dr. Keiper's laboratory, as well as Masters and undergraduate students from ECU's Biology and Chemistry departments. As in the past granting period, the project also involves collaborators and students from other universities and high schools with an interest in molecular gene expression during development. The research capitalizes on the lab's experience in the biochemistry of mRNA translation and provides broad laboratory training in molecular techniques, genetics and transgenesis to young scientists. These students find the C. elegans system both tractable and significantly more accessible intellectually than mammalian systems. They receive the greatest educational benefit from first-hand involvement in new discoveries as well as opportunities to present their findings and publish their accomplishments in scientific journals. In recent years, several students who participated in this project have taken positions in the biotechnology industry or entered graduate research/medical professional academic programs.

细胞开始生长和分裂（增殖）或改变其命运（分化）需要新的基因表达。 卵子和精子（配子）的发育同样涉及基因表达和分化的关键时期。 早期细胞分裂，然后分化成精子或卵母细胞。 基因转录在配子发生的早期是活跃的，但随着细胞进入减数分裂而变得沉默，因此在增殖期储存的mRNA成为产生新蛋白质的唯一手段。 在卵母细胞、精母细胞或胚胎中，发育重要的mRNA被翻译成核糖体上的蛋白质，并且新的蛋白质指导继续分化或细胞死亡（凋亡）。 该研究项目的重点是被称为eIF 4因子的蛋白质，这些因子与mRNA接触，作为将它们招募到蛋白质合成机制的第一步。 具体而言，将研究导致配子和胚胎中新蛋白质合成的eIF 4因子的活性。 动物模型系统，如土壤线虫，秀丽隐杆线虫，在这项研究中是必不可少的，因为它们通常比人类胚胎简单。 梭线虫胚胎从受精卵发育成有组织的多细胞胚胎，其方式与高等动物非常相似。 幸运的是，这些蠕虫的身体结构要简单得多，只有一些肌肉、神经元、消化和生殖器官。 更重要的是，在这个简单的模型系统中，所需的关键基因非常相似。 因为蛋白质合成机制在动物中是很保守的，使用C。更广泛的影响和教育效益：该项目直接影响了少数民族和一名正在完成博士学位的女研究生的教育。Keiper博士实验室的论文研究以及ECU生物和化学系的硕士和本科生。 与过去的资助期一样，该项目还涉及来自其他大学和高中的合作者和学生，他们对发育过程中的分子基因表达感兴趣。 该研究利用了实验室在mRNA翻译生物化学方面的经验，并为年轻科学家提供了分子技术，遗传学和转基因方面的广泛实验室培训。 这些学生找到了C。与哺乳动物系统相比，秀丽隐杆线虫的系统既易驾驭，又明显更容易理解。 他们从亲身参与新发现以及有机会在科学期刊上展示他们的发现和发表他们的成就中获得最大的教育利益。 近年来，参与该项目的几名学生已在生物技术行业任职或进入研究生研究/医学专业学术课程。