? ? Modern biology research relies extremely heavily on transgenic tools. This is true of virtually all model systems that are being used to explore questions as diverse as the cell biology of mouse brain development to the highly specialized antigenic variation-based immunological defenses of human pathogens like trypanosomes. In the last five years, rapid advances in transposon and integrase molecular engineering and recombinant DNA technology have led to the development of sophisticated transposon and integrase based transgenic techniques for many model systems. These tools include efficient transposons for zebrafish, efficient site- specific integration systems for Drosophila as well as a new generation of genome engineering tools for mice. These advances have not been applied to all common model systems. In particular, few improvements have been made in transgenic methodologies for the C. elegans model system. Development of these tools is critical to leveraging the substantial genetic, molecular, and intellectual resources that have already been committed to develop this promising model system. This grant proposes to develop molecular genetic resources by testing the feasibility of using two mobile genetic elements for creating transgenic nematodes. The utility of these tools will include the improved ability to create mutations to study gene function, to create gene reporters for cell biological analysis, and to create transgenic animals for the study of basic cellular processes that underlie the cause of many human diseases. ? ? Public Health Relevance: This grant proposes to develop transgenic tools for a model system used in the study of basic cellular processes that underlie human disease. The contributions of this model system to understanding disease include the discoveries of several biological processes each of which was recently recognized by a Nobel prize. The first discovery is that of programmed cell death which plays critical roles in cellular responses to stroke. The second is the discovery of the process of RNA interference that is widely recognized as very promising methodology to treat human diseases such as cancer that result from the mis-expression of genes. Basic research such as the work proposed herein is essential for long-term progress in public health. ? ? ?
