Our research objective has been to understand, at the molecular level, the regulation of information transfer in mammalian cells and developing organisms. A deeper analysis of this process will require new tools and approaches. The ability to introduce modified genes into living organisms appears to be such an approach. As a first step we propose to study DNA-mediated transformation of cultured mammalian cells using glass micropipettes to directly inject DNA into cell nuclei. We will construct plasmid vectors which facilitate integration of exogenous genes into the host chromosome. How and where the injected DNA integrates into the host chromosome will be determined. The technology will then be extended to introduce genes into early mouse embryos. The expression and germline transmission of the injected genes in adult mice will be tested. It is hoped that this approach will allow the controlled introduction of modified genes into a developing organism and thereby systemtically alter its developmental program. If such a scenario becomes reality, then complex questions concerning morphogenesis can be answered. There are entirely different reasons for attempting to introduce genes back into living animals. In man over 2000 diseases of known genetic origin have been identified. However, the relationship between the manifestations of the disease and the missing product is often not clear. The availability of animal models for human genetic disease should accelerate an understanding of this cause and effect relationship. Because of the limitations imposed by mutation frequencies one cannot go out and readily find such animal models; it may be easier to create them.
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