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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、B型肝炎病毒感染癌症发展和对抗癌药物、胰岛素调节的葡萄糖代谢和营养素的敏感性体内平衡激酶家族的成员是广泛感兴趣的主题，因为它们具有潜在的作为各种人类疾病的治疗靶点。尽管它们的重要性和疾病相关性，关于LAMMER相关激酶携带的机制存在相当大的知识缺口，出其功能。基于以前对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，这些数据涉及与LAMMER相关的裂变酵母成员。激酶Dsk 1和Kic 1/Lkh 1在mRNA核输出和着丝粒基因沉默中的作用。的首要目标这项研究的目的是揭示Dsk 1和Kic 1激酶新作用的分子基础在mRNA输出和着丝粒基因沉默中。这些实验是为了验证假设， Dsk 1和Kic 1可能通过调节poly（A）结合活性在基因表达中发挥新的作用 Pabp蛋白参与mRNA输出并参与着丝粒基因的Swi 6/HP 1磷酸化级联反应沉默将采用分子遗传学、生物化学和荧光显微镜来评估体内受激酶影响的Pabp和Swi 6蛋白的磷酸化和细胞定位，以及确定Dsk 1/Kic 1与Pabp或Swi 6之间可能的激酶-底物关系。裂殖酵母粟酒裂殖酵母是一个基因组较小的遗传和细胞生物学上易于处理的系统冗余度小，提供了一个有价值的模式生物解剖多方面的激酶功能。实现该研究的目标不仅将为LAMMER激酶的分子机制提供见解，在所有真核生物中起作用，而且有助于阐明所涉及疾病的分子病理学，为开发治疗方法揭开更多的靶点。该项目将为未来的长期发展奠定基础。长期研究，以最终解决激酶功能在多个步骤中的相互作用，真核基因表达和细胞分裂周期，其保真度是癌症预防的中心问题和治疗。此外，该提案的教育目标与具体的研究的目的是将项目融入课程调查，以提高学生对项目主题，并鼓励妇女和科学界代表性不足的群体参与 research.该项目旨在为学生在以下领域的研究经验提供重要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在健康相关领域工作。无论是拟议的研究的意义和加强在科学教育的研究成分加强了凯克科学的研究环境系和克莱蒙学院。