T-TYPE CYCLIN/CDK9 COMPLEXES IN T CELL ACTIVATION

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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.