Transgenic Animal Model Development Core
Description
The Transgenic Mouse Resource Core is designed to support investigators doing biology of aging research by creating mice that have been genetically altered by either inserting a new gene or removing a normal gene. This method has become one of the most exciting approaches to discovering the functions and interactions of genes in mammals. At the University of Washington Nathan Shock Center, this transgenic technology is used to develop new animal models for studying genetic mechanisms of the aging process.During the previous year, transgenic mouse production has focused on constructs with enhanced defense against free radical injury in aging (e.g., catalase, superoxide dismutase, glutathione S-transferase), Werner Syndrome, adult onset diabetes, Alzheimer's Disease, thrombospondin, and rheumatoid arthritis in aging. Almost 4000 embryos, mainly of the C57BL/6 ingred strain, have been transferred, 498 pups analyzed and at least 40 contained the integrated construct. In addition, this core concentrated an appreciable portion of effort into embryonal stem line (ES) methodologies for generation of knockouts and targeted ES transgenics. This included work to generate mouse models of Werner's Syndrome, models for study of presenillin genes related to Alzheimer's Disease and study of models of thrombospondin in aging. In the past year, a total of 396 embryos were transferred, and 79 pups were born, of which 37 were chimeric.
Background
The isolation of mammalian genes is of utmost importance to the biology and medicine of aging because of the contributions these studies can make to the understanding of physiology and development. Techniques for introducing foreign genes into the mouse germ line provide novel approaches for modeling human genetic and chronic degenerative diseases.Since the initial report in 1980 describing transgenic mice, methods for the direct microinjection of DNA into the pronuclei of fertilized embryos have become established. Foreign genes can be incorporated into somatic germline tissues, with expression of these elements in the progeny of founder mice. The creation of "transgenic" animals that make a specified gene product presents a spectrum of opportunities for basic studies in molecular pathogenesis and pre-clinical investigations applicable to a wide variety of medical problems of aging.
An additional gene transfer technology developed in the 1980's involved the use of stem cells from the early embryo, so-called embryonic stem (ES) cells. The capacity of ES cells to undergo differentiation makes them useful for investigating the effects of genetic modifications of either the gain of function or loss of function. These pluripotent genetically modified ES cells can then be used to make mice with deleted genes (gene knockout) or targeted mutagenesis of genes thought to be involved in the aging process. It is also possible to develop lines of transgenic mice carrying very large DNA constructs (>600 kb) transfected into ES cells. The University of Washington Aging Program provides a focused level of expertise and resources to enhance and facilitate the development of transgenic animal models using ES cell transfer technology.