The applicant is a neuroimmunologist with molecular biology experience and an interest in immune cell growth and differentiation mechanisms. His training as a neuroimmunologist was completed at the Brigham and Women's Hospital (BWH), Boston, MA. He is a member of the BWH Cancer Center. He also holds an appointment as a Neurology Instructor at Harvard Medical School. His interest is now focused on the function of histone deacetylase 3 (HDAC3), a member of a family of genes implicated in leukemia, that he cloned under his own initiative in the sponsor's laboratory. The scientific goal of this proposal is to understand the subcellular pathways implicated in HDAC3 function. Our hypothesis is that HDAC3 is part of an immunoregulatory nuclear molecular complex and its aberrant expression could lead to cell cycle dysregulation and abnormal growth. The Specific Aims are: 1) generate HDAC3 mutants and chimeras with altered enzymatic or protein-binding activity, 2) identify functional consequences of HDAC3 mutant overexpression on mediation of transcriptional repression of targeted reporter genes, cell cycle progression and differentiation of mammalian cells, and 3) clone and characterize the mouse HDAC3 genomic locus to generate HDAC3-knockout mice for an in vivo analysis of its function. The applicant's training in molecular biology and cell immunology has allowed him to explore the critical regulatory role that HDAC3 plays in cell growth and differentiation. He realizes, however, that in order to answer the next set of questions regarding HDAC3 function, he needs additional training. The Mentored Clinical Scientist Development Award will provide the crucial means for a complementary protein biochemistry and gene knockout technology training period necessary for achieving independence in a cancer research career. The sponsor's laboratory provides an ideal environment to accomplish the aims of this project because of its strong biochemistry and genetics background, the collaborative momentum it has achieved, and its exemplary didactic and ethical curriculum. After completing this project, the applicant will competitively examine the in vivo function of HDAC3 in murine hematologic cells, and its role in malignancies (leukemia/lymphomas) that infiltrate the nervous system.