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: 6510221
• 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/6510221
• 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（改编自申请）：该申请提出了一项计划 促进 Xavier Grana 博士的研究事业。他的目标是实现 卓越的研究和研究生教学。这 此申请的目的是为候选人获得薪资支持 为期五年，允许延长小学期限 将他从工作中解放出来，专注于研究和相关活动 增加了医学院的教学和服务负担。短期 研究目标是实现他目前资助的研究中提出的目标 申请包括 NIAID 的 RO1 拨款、提交的拨款 更新 W.W.史密斯慈善信托基金和 NIGMS 的 R29。 Grana 博士是一位分子生物学家和生物化学家。 Grana 博士是一名研究人员 在菲尔斯研究所担任助理教授两年。 1996年12月 他被晋升为目前的终身教授助理教授 天普大学医学院生物化学系。 一个 提出职业发展计划，以加强研究计划 候选人。该奖项将使候选人能够推进他的研究 及时掌握各个相关领域的能力和专业知识 通过扩大他的团队规模来扩展他的研究计划 研究生和技术人员。此外，候选人计划 通过参加一些活动来提高他的研究和学术技能 与候选人寻求的领域相关的研讨会和讲习班 获得额外的专业知识并通过与一些资深人士的互动 天普大学医学院的研究人员。研究计划 本质上是寻求实现候选人资助中提出的具体目标 RO1 和 R29 拨款以及向 W.W. 提交的更新拨款申请。史密斯 慈善信托。合并后的具体目标如下： 第一， 阐明导致个体T型上调的机制 T 细胞活化和分化过程中的细胞周期蛋白/CDK9 复合物 沿单核细胞/巨噬细胞谱系的骨髓细胞。其次，要建立 每个个体 T 型细胞周期蛋白在多大程度上有助于 HIV 产生 在新感染的单核细胞/巨噬细胞以及单核细胞和巨噬细胞中复制 T 细胞携带整合的潜在 HIV 原病毒基因组。这两个目标是 进行。三、评估一系列腺病毒的有效性 编码多种 T 型细胞周期蛋白突变体，无需干预即可阻断 HIV 复制 干扰新感染者的正常细胞生理机能 单核细胞/巨噬细胞以及含有潜伏 HIV 的单核细胞和 T 细胞 整合原病毒。四、定义T型cyclintCDK9的作用 通过识别 T 细胞激活和骨髓分化中的复合物 他们的下游靶基因。最终目标是精确定义 视网膜母细胞瘤相关蛋白 pl30（激酶）上的磷酸化位点 差异磷酸化的参与及其生物学意义 该蛋白质在细胞周期进入/退出转变时的作用。天普大学 医学院、生物化学系和费尔斯研究所 癌症研究全力支持这一应用并提供一个环境 候选人研究生涯的持续发展。 职业发展计划：该计划写得很好并且符合 候选人的职业目标；它提供了更多的时间进行研究和 与其他活跃的艾滋病毒研究研究者合作。 IRG 是 关心候选人将有多少时间用于研究。基于 关于候选人将继续获得 K02 奖的活动，他将 未达到该奖项要求的 75% 研究努力。请参阅下面的评论。 研究计划：拟议的研究重点是T型细胞周期蛋白和 CDK9 对 T 细胞和巨噬细胞中 HIV 复制的影响，以及它们的作用 T 细胞激活和骨髓分化的复合物。科学和 该研究的技术价值很高。实验很清楚 已定义，主要是假设驱动的，并且有可能产生重大影响 对文学的贡献。该研究得到研究经费的支持， R01、R29 和 W.W. 的资助史密斯基金会。查看评论 以下。