The etiology and pathogenesis of type-1 diabetes remain enigmatic. Phenomenal recent advances in genetics and genomics research have offered the hope that a genetic dissection of diabetes susceptibility and its manifestations will provide a shortcut to a greater understanding of this devastating disease. However, like that of many other autoimmune disorders, the genetics of diabetes in both humans and mice has proven extraordinarily complex, greatly impeding efforts to identify susceptibility loci. The goal of this Pilot and Feasibility project, a collaborative effort between one lab with expertise in the field of type-1 diabetes and another at the forefront of the zebrafish genetics field, is to provide proof-of-principle for the concept that one can exploit the power of zebrafish genetics to identify novel diabetes-susceptibility candidate genes. The hypothesis is that it will be possible to identify genes predisposing to autoimmunity, in particular to autoimmune diabetes, by random mutagenesis of zebrafish spermatagonia, selection of offspring with aberrant patterns of T cell circulation (reflecting abnormal autoactivation), and cloning of the mutated loci by positional and candidate gene approaches. Milestones will be 1) establishment of a performant system for visualizing T cells circulating in zebrafish, and 2) completion of a pilot mutagenesis/screen to demonstrate our ability to obtain such mutants, and to assess their frequency. Future prospects include functional analysis of any novel genes identified and extrapolation of significant discoveries to the murine and human systems.
| Langenau, David M; Ferrando, Adolfo A; Traver, David et al. (2004) In vivo tracking of T cell development, ablation, and engraftment in transgenic zebrafish. Proc Natl Acad Sci U S A 101:7369-74 |
| Trede, Nikolaus S; Langenau, David M; Traver, David et al. (2004) The use of zebrafish to understand immunity. Immunity 20:367-79 |
| Traver, David; Herbomel, Philippe; Patton, E Elizabeth et al. (2003) The zebrafish as a model organism to study development of the immune system. Adv Immunol 81:253-330 |
