MOLECULAR CHARACTERIZATION OF MCLI PCNA INTERACTION

藤濑博士的长期目标是作为一名分子生物学家和心脏病学家，其主要重点是利用分子生物学方法预防和治疗心血管疾病。 在Edward T.H.博士的指导和指导下，是的，藤濑博士在细胞凋亡调控领域进行了研究。 在描述Bcl-2同源物MCL 1（ML 1髓细胞白血病）的过程中，Fujise博士发现了MCL 1和PCNA（增殖细胞核抗原）之间的新相互作用。 PCNA是一种29 kDa的核蛋白，参与DNA修复和复制以及细胞增殖和分化。 PCNA在系统性红斑狼疮（SLE）、血管成形术后再狭窄等疾病的发病机制中起重要作用。 细胞凋亡及其缺乏在许多人类疾病中起关键作用，包括癌症、艾滋病、心肌炎、动脉粥样硬化和心肌梗死。MCL 1与PCNA的相互作用可能是抗凋亡蛋白与细胞周期蛋白之间的重要分子联系。 基于MCL 1通过与PCNA的相互作用在DNA修复和复制以及细胞增殖和分化中发挥作用的假设，Fujise博士在此提出了在该奖项的五年中描述MCL 1-PCNA相互作用的特征。 首先，Fujise博士将使用酵母双杂交系统进一步表征MCL 1-PCNA相互作用的生化方面。其次，Fujise博士将研究MCL 1-PCNA相互作用的功能意义，包括MCL 1过表达对细胞增殖的影响以及在PCNA存在下MCL 1对DNA聚合酶δ、DNA甲基化酶和DNA修复酶的影响。 最后，将评估细胞周期阶段、磷酸化和DNA损伤对MCL 1-PCNA相互作用和MCL 1的亚细胞定位的影响。 在叶博士的指导下，藤濑博士将在人类疾病预防分子医学研究所的心血管疾病研究中心进行研究，将80%的专业时间投入到研究中。 研究中心和研究所将为藤濑博士提供一个高度互动和富有成效的环境，以及他的研究所需的所有设备。 科学顾问委员会由三名资深科学家组成，包括导师将指导藤濑博士的科学进展。 在这个奖项完成后，藤濑博士将是一个独立的，高生产力的研究者，在细胞凋亡调控和心脏疾病的预防和治疗领域做出重要贡献的可能性很高。

Dr. Fujise's long-term objectives is to serve as a molecular biologist and cardiologist, whose main focus is prevention and treatment of cardiovascular diseases using molecular biological approach. Under the guidance and direction of Dr. Edward T.H. Yeh, Dr. Fujise has performed the research in the field of apoptosis regulation. In the process of characterizing MCL1(ML1 myeloid cell leukemia), a Bcl-2 homologue, Dr. Fujise discovered a novel interaction between MCL1 and PCNA (Proliferating cell nuclear antigen). PCNA is a 29kDa nuclear protein involved in DNA repair and replication and cell proliferation and differentiation. The role of PCNA has been implicated in pathogenesis of SLE (Systemic lupus erythematosis), restenosis after angioplasty and others. Apoptosis as well as the lack of it play critical roles in many human diseases including cancer, AIDS, myocarditis, atherosclerosis and myocardial infarction. The MCL1-PCNA interaction may be an important molecular link between anti-apoptotic proteins and cell cycle proteins. Based on the hypothesis that MCL1 plays a role in DNA repair and replication and cell proliferation and differentiation through its interaction with PCNA, Dr. Fujise here proposes to characterize the MCL1-PCNA interaction over the five years of the Award. First, Dr. Fujise will further characterize biochemical aspects of MCL1-PCNA interaction, using yeast two hybrid system. Second, Dr. Fujise will investigate the functional significance of the MCL1-PCNA interaction, including the effect of MCL1 over- expression on cell proliferation and the effect of MCL1 on DNA polymerase delta, DNA methylase, and DNA repair enzymes in the presence of PCNA. Finally, the impact of cell cycle phases, phosphorylation and DNA damage on MCL1-PCNA interaction and MCL1's subcellular localization will be evaluated. With Dr. Yeh as his Mentor, Dr. Fujise will perform his research at Research Center for Cardiovascular Diseases within the Institute of Molecular Medicine for Prevention of Human Diseases, devoting 80 percent of his professional time to the research. The Research Center and Institute will provide Dr. Fujise with a highly interactive and productive environment as well as with all the equipment needed for his research. The Scientific Advisory Committee, consisting of three senior scientists including the mentor will guide Dr. Fujise's scientific progress. At the completion of this Award, Dr. Fujise will be an independent, highly productive investigator with a high likelihood of making critical contributions in the fieled of apoptosis regulations and in prevention and treatment of cardiac diseases.