T-TYPE CYCLIN/CDK9 COMPLEXES IN T CELL ACTIVATION

T 细胞激活中的 T 型细胞周期蛋白/CDK9 复合物

• 批准号: 6372715
• 负责人: Xavier Grana
• 金额: $ 10.45万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-15 至 2005-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6372715
• 关键词: Adenoviridae; HIV infections; T lymphocyte; cell differentiation; clinical research; cyclin dependent kinase; cyclins; human subject; leukocyte activation /transformation; macrophage; monocyte; phosphorylation; training

DESCRIPTION (adapted from the application): This application proposes a plan to enhance the research career of Dr. Xavier Grana. His goals are to achieve excellence in research as well as in teaching at the graduate level. The objective of this application is to obtain salary support for the candidate for a period of five years allowing for an extended period of primary concentration in research and related activities by releasing him from an increased teaching and service load at the Medical School. The short-term research goals are to meet the aims proposed in his currently funded application including an RO1 grant from the NIAID, a grant submitted for renewal to the W.W. Smith Charitable Trust and an R29 from NIGMS. Dr. Grana is a Molecular Biologist and Biochemist. Dr. Grana was a Research Assistant Professor at the Fels Institute for two years. In December of 1996 he was promoted to his current position of tenure-track Assistant Professor in the Department of Biochemistry at Temple University School of Medicine. A career development plan is proposed to enhance the research program of the candidate. The award will allow the candidate to advance in his research abilities and expertise in various related fields in a timely-fashion as well as to extend his research program by increasing the size of his group with graduate students and technical staff. In addition, the candidate plans to enhance his research and academic skills by participating in a number of Symposia and workshops related to the fields in which the candidate seeks to gain additional expertise and by interacting with a number of senior researchers at Temple University School of Medicine. The research plan essentially seeks to meet the specific aims proposed in the candidate's funded RO1 and R29 grants and a renewal grant application submitted to the W.W. Smith Charitable Trust. The combined specific aims are as follows: First, To elucidate the mechanisms leading to upregulation of individual T-type cyclin/CDK9 complexes during both T cell activation and differentiation of myeloid cells along the monocyte/macrophage lineage. Second, to establish to which extent each individual T-type cyclin contributes to HIV productive replication in newly infected monocytes/macrophages and in both monocytes and T cells harboring integrated latent HIV proviral genomes. These two aims are underway. Third, to assess the effectiveness of a series of adenoviruses encoding various T-type cyclin mutants in blocking HIV replication without interfering with normal cellular physiology in both newly infected monocyte/macrophages and monocytes and T cells containing latent HIV integrated proviruses. Fourth, to define the role of T-type cyclintCDK9 complexes in T cell activation and myeloid differentiation by identifying their downstream target genes. The final aim is to define precisely the phosphorylation sites on the retinoblastoma related protein pl30, the kinases involved and the biological significance of the differential phosphorylation of this protein at the cell cycle entry/exit transitions. Temple University School of Medicine, the Department of Biochemistry and the Fels Institute for Cancer Research fully support this application and provide an environment for the continued development of the research career of the candidate. Career Development Plan: The plan is well written and consistent with the candidate's career goals; it affords increased time for research and collaboration with other active investigators in HIV research. The IRG is concerned about the amount of time the candidate will have for research. Based on the activities that the candidate will continue with a K02 award, he will not meet the 75% research effort required by this award. See comments below. Research Plan: The proposed research centers on the role of T-type cyclins and CDK9 on HIV replication in T cells and macrophages, and on the roles of these complexes in T cell activation and myeloid differentiation. The scientific and technical merits of the research are high. The experiments are clearly defined, largely hypothesis driven, and have potential for significant contributions to the literature. The research is supported by research grants, an R01, an R29, and a grant from the W.W. Smith Foundation. See comments below.

描述（改编自应用程序）：此应用程序提出了一个计划 来提升泽维尔·格拉纳博士的研究事业他的目标是实现 卓越的研究以及在研究生水平的教学。的 此申请的目的是为候选人获得工资支持 为期五年，允许延长小学教育时间， 集中精力从事研究和相关活动， 增加了医学院的教学和服务负荷。短期 研究目标是满足他目前资助的目标， 申请包括来自NIAID的RO 1赠款， 更新到W.W.史密斯慈善信托基金和NIGMS的R29。 Grana博士是分子生物学家和生物化学家。格拉纳博士是一名研究人员 在费尔斯研究所担任助理教授两年。1996年12月 他被提升到他目前的终身助理教授的位置， 天普大学医学院生物化学系。 一 职业发展计划提出，以加强研究计划的 候选人该奖项将允许候选人在他的研究进步 能力和专业知识，在各个相关领域及时，以及 为了扩大他的研究计划， 研究生和技术人员。此外，候选人还计划 通过参加一些提高他的研究和学术技能， 与候选人寻求的领域有关的研讨会和讲习班 获得更多的专业知识，并与一些高级 天普大学医学院的研究人员。研究计划 基本上是为了满足候选人资助的具体目标， RO 1和R29赠款以及向W.W.提交的续期补助金申请。史密斯 慈善信托。具体目标如下：第一， 阐明导致个体T-型表达上调的机制 细胞周期蛋白/CDK 9复合物在T细胞活化和分化过程中的作用 沿着单核细胞/巨噬细胞谱系的髓样细胞。第二，建立 每一个T型细胞周期蛋白在多大程度上促进了HIV的产生 在新感染的单核细胞/巨噬细胞中以及在单核细胞和 T细胞携带整合潜伏HIV前病毒基因组。这两个目标是 正在进行中第三，评估一系列腺病毒的有效性 编码各种T型细胞周期蛋白突变体，阻断HIV复制， 干扰了新感染的 单核细胞/巨噬细胞和单核细胞和T细胞含有潜伏的HIV 整合前病毒。第四，明确T型细胞周期蛋白CDK 9的作用 通过鉴定T细胞活化和髓样分化中的复合物 它们的下游靶基因最终目的是精确定义 视网膜母细胞瘤相关蛋白P130上的磷酸化位点， 以及差异磷酸化的生物学意义 这种蛋白质在细胞周期进入/退出转换。坦普尔大学 医学院，生物化学系和费尔斯研究所 癌症研究完全支持这一应用程序，并提供一个环境， 候选人研究生涯的持续发展。 职业发展计划：该计划写得很好，并与 候选人的职业目标;它提供了更多的时间进行研究， 与其他活跃的艾滋病毒研究人员合作。IRG是 关注候选人将有多少时间进行研究。基于 关于候选人将继续获得K 02奖的活动，他将 没有达到这个奖项所要求的75%的研究工作。见下文评论。 研究计划：拟议的研究中心是T型细胞周期蛋白的作用， CDK 9对T细胞和巨噬细胞中HIV复制的影响，以及这些作用 复合物在T细胞活化和髓样分化中的作用。科学和 这项研究的技术价值很高。这些实验显然 定义，主要是假设驱动，并有潜力显着 对文学的贡献。这项研究得到了研究赠款的支持， R 01、R29和WW的资助史密斯基金会见评论 下面