The zebrafish, Danio rerio, has emerged as an important vertebrate model system for the study of development. Thousands of developmental mutants have been generated via ENU and insertional mutagenesis screens, and, importantly, the majority of the genes responsible for these mutant phenotypes have human counterparts that may give rise to corresponding aberrant conditions and birth defects. While this augurs well for the zebrafish model, the onus is now on the community to use the tremendous potential offered in this system to address problems of biomedical relevance. This sentiment was recently articulated in a communal White Paper to NIH, """"""""Zebrafish as a model system to study and cure human disease"""""""" (see Appendix). The overriding objective of this R24 competitive renewal is to provide genomic resources and infrastructure to individual investigators in order to help move the community into more function-based and goal-driven biology as mandated by the White Paper. Specifically, we will: (1) maintain a communal BAC and large-insert screening resource to aid investigators with isolation of genomic clones from unrepresented or difficult-to-clone regions;(2) improve the efficacy of BAC transgenesis of zebrafish embryos using an empirical and systematic approach;(3) generate BAC-reporter transgenic lines for the community for genes;of immunological importance;and (4) provide a training environment and research opportunities for undergraduate interns and science teachers. The core- and resource-type activities proposed in this application are in keeping with the R24 grant mechanism at NCRR and are logical extensions of the work performed during the previous funding cycle of this grant. Based on the discussion with prominent zebrafish researchers as well as queries of the current zebrafish genome project databases, we believe there is a pressing need for such BAC communal resources and that our laboratory is well-suited to fulfill this role given our expertise in BAC construction and the fact that existing equipment and infrastructure are already it place for handling and manipulating large-insert clones. In this revised application, we have specifically addressed major concerns raised by the previous Study Section with respect to Aims 1 and 4. In summary, our proposed activities are aimed at facilitating zebrafish researchers to address medically relevant research problems. We will do this by generating genomic resources that will be of wide use to the community and which will allow investigators to more easily create animal models of human disease. These models are important as they allow basic investigation into disease mechanism and intervention. In addition in keeping with the educational mission of NCRR, science outreach will be established for undergraduates and science teachers through partnerships with local educational and science outreach programs.
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