Novel Functions of LAMMER-related Kinases in Gene Expression

LAMMER 相关激酶在基因表达中的新功能

基本信息

批准号：
9377046
负责人：
ZHAOHUA TANG
金额：
$ 41.24万
依托单位：
CLAREMONT MC KENNA COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-08 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9377046
关键词：
Address Affect Alpha Cell Animal Model Antineoplastic Agents Apoptosis Area Biochemical Biochemistry Biological Biological Assay Cell Cycle Cell Cycle Regulation Cell Nucleus Cell Proliferation Cell physiology Cellular biology Centromere Chromosome Segregation Data Development Disease Education Environment Eukaryota Event Evolution Family Family member First Generation College Students Fission Yeast Fluorescence Microscopy Foundations Funding Future Gene Expression Gene Silencing Genetic Genetic Transcription Genome Goals Health Hepatitis B Homeostasis Human Impairment Insulin Investigation Knowledge Laboratories Learning Light Malignant Neoplasms Mammals Mediating Messenger RNA Methodology Mitosis Modeling Molecular Molecular Genetics Nuclear Export Nutrient Organism Orthologous Gene Pathway interactions Phosphorylation Phosphotransferases Play Poly(A)-Binding Proteins Process Protein Kinase Protein Tyrosine Kinase Proteins Public Health RNA Splicing Regulation Research Research Personnel Research Project Grants Role Science Serine Signal Transduction Students System Testing Therapeutic Threonine Underrepresented Groups Virus Diseases Woman Women&apos s Group Work Yeasts base cancer prevention cancer therapy cell growth college design disorder prevention experience experimental study glucose metabolism heterochromatin-specific nonhistone chromosomal protein HP-1 human disease improved in vivo insight interest mRNA Export mRNA Precursor member molecular pathology next generation novel prototype science education summer research synergism therapeutic development therapeutic target tool tumorigenesis undergraduate research undergraduate student

项目摘要

LAMMER-related kinases play major roles in cell growth, differentiation, hepatitis B virus infection, cancer development and sensitivity to anti-cancer drugs, insulin-regulated glucose metabolism and nutrient homeostasis. Members of the kinase family are subjects of extensive interest because of their potential to serve as therapeutic targets for various human diseases. Despite their importance and disease relevance, considerable gaps of knowledge exist regarding the mechanisms by which the LAMMER-related kinases carry out their functions. Building upon previous work on their functions in cell cycle control and pre-mRNA splicing, the PI's laboratory obtained preliminary data that implicate the fission yeast members of the LAMMER-related kinases, Dsk1 and Kic1/Lkh1, in nuclear export of mRNA and centromeric gene silencing. The primary goal of the proposed research is to decipher the molecular basis underlying the novel roles of Dsk1 and Kic1 kinases in mRNA export and centromeric gene silencing. The experiments are designed to test the hypothesis that Dsk1 and Kic1 may execute their novel roles in gene expression by modulating the activity of poly(A)-binding protein Pabp in mRNA export and participating in Swi6/HP1 phosphorylation cascade for centromeric gene silencing. Molecular genetics, biochemical and fluorescence microscopy will be employed to assess in vivo phosphorylation and cellular localization of Pabp and Swi6 proteins affected by the kinases, as well as to determine the possible kinase-substrate relationship of Dsk1/Kic1 with Pabp or Swi6. The fission yeast Schizosaccharomyces pombe, as a genetically and a cell biologically tractable system with small genome size of less redundancy, offers a valuable model organism to dissect the multifaceted kinase functions. Achieving the goal of the research will not only provide insights into the molecular mechanisms of LAMMER kinase function in all eukaryotes but also contribute to elucidation of molecular pathology of the diseases involved and unraveling more targets for developing therapeutics. The proposed project will lay the foundation for the long- term investigation to ultimately address the interplay between the kinase functions in multiple steps of eukaryotic gene expression and cell-division cycle, the fidelity of which is the central issue of cancer prevention and treatment. Furthermore, the educational objectives of the proposal are intertwined with the specific research aims to integrate the project into course-based investigation, to enhance students' understanding of the project themes, and to encourage women and underrepresented groups in science to participate in research. This project aims to provide crucial opportunities for student research experience in the areas relevant to public health, stimulate their interest in sciences, and diversify the next-generation of professionals working in health-related fields. Both the significance of the proposed research and the enhancement in investigative components of science education strengthen the research environment of the Keck Science Department and the Claremont Colleges.

LAMMER 相关激酶在细胞生长、分化、乙型肝炎病毒感染、癌症的发展和对抗癌药物、胰岛素调节的葡萄糖代谢和营养的敏感性体内平衡。激酶家族的成员因其潜在的作为多种人类疾病的治疗靶点。尽管它们很重要并且与疾病相关，关于 LAMMER 相关激酶携带的机制存在相当大的知识空白出他们的功能。基于之前关于它们在细胞周期控制和前 mRNA 剪接中的功能的研究， PI的实验室获得了初步数据，表明LAMMER相关的裂殖酵母成员激酶 Dsk1 和 Kic1/Lkh1 参与 mRNA 核输出和着丝粒基因沉默。主要目标是拟议的研究旨在破译 Dsk1 和 Kic1 激酶新作用的分子基础 mRNA 输出和着丝粒基因沉默。这些实验旨在检验以下假设： Dsk1 和 Kic1 可能通过调节 Poly(A) 结合活性来发挥其在基因表达中的新作用蛋白质 Pabp 参与 mRNA 输出并参与着丝粒基因的 Swi6/HP1 磷酸化级联沉默。将采用分子遗传学、生化和荧光显微镜来评估体内受激酶影响的 Pabp 和 Swi6 蛋白的磷酸化和细胞定位，以及确定 Dsk1/Kic1 与 Pabp 或 Swi6 可能的激酶-底物关系。裂殖酵母粟酒裂殖酵母，作为基因组大小较小的遗传和细胞生物学易处理系统冗余较少，提供了一个有价值的模型生物体来剖析多方面的激酶功能。实现该研究的目标不仅是深入了解 LAMMER 激酶的分子机制在所有真核生物中发挥功能，而且还有助于阐明所涉及疾病的分子病理学阐明开发治疗方法的更多目标。拟建项目将为长远发展奠定基础术语研究最终解决多个步骤中激酶功能之间的相互作用真核基因表达和细胞分裂周期，其保真度是癌症预防的核心问题和治疗。此外，该提案的教育目标与具体的教育目标交织在一起。研究旨在将项目融入基于课程的调查，以增强学生对项目主题，并鼓励妇女和科学界代表性不足的群体参与研究。该项目旨在为学生在这些领域的研究经验提供重要的机会与公共卫生相关，激发他们对科学的兴趣，并使下一代专业人员多样化从事健康相关领域的工作。拟议研究的意义和增强科学教育的研究部分加强了凯克科学的研究环境系和克莱蒙特学院。