The long-term goals of this research project are to understand the role of NASP (nuclear autoantigenic sperm protein) in the regulation of gene expression and cell cycle progression. NASP is a linker (Hi) histone chaperone that interacts with binding partners in a molecular complex on the nucleosome, binds HSPyo-2 and Hit in spermatogenic cells and associates with Kuyo/8o and DNA-PK in DNA repair. Over the past four years our hypothesis that NASP is important for normal cell function during both mitosis and meiosis has been abundantly supported by our new data and data from several other laboratories. Our data demonstrate that NASP is absolutely required for cell cycle progression and embryonic development and that NASP's transport and regulation of Hi histones may be critical for the expression of a number of genes. To continue our study of NASP, the Specific Aims of this proposal are:
Specific aim #1. This aim will test the hypothesis that NASP functions in steroid receptor regulation of gene transcription by controlling the level of Hi in chromatin. To test this hypothesis we will (i) collaborate with Projects I and II to study the expression of NASP in relation to the expression and transcriptional activities of steroid receptors in the ovary and endometrium of normal fertile women and women with polycystic ovarian syndrome. In the second part of this specific aim we will (2) determine whether NASP is present in chromatin nucleosomal complexes bound to Hi histones and DNA and whether post-translational modification of Hi influences its binding to NASP.
Specific aim #2. This aim will test the hypothesis that (i) during spermatogenesis tNASP is associated with a chromatin nucleosomal complex that includes HSPyo-2, which signals the cell that it may transition from G2 to M, and that (2) in spermatogenic cells a [tNASP-Hi] complex is associated with Kuyo/KuSo/DNA-PK coincident with chromatin remodeling that repairs double strand DNA breaks and avoids apoptotic responses of spermatocytes and spermatids.
Specific aim #3. This aim will test the hypothesis that NASP expression in germ cells is required for spermatogenesis. To test this hypothesis we will generate a conditional knockout mouse model designed to ablate NASP when it is normally expressed during spermatogenesis. This research will contribute to our understanding of gene regulation and in particular will help understand the inappropriate'gene expression in PCOS patients.
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