Microsurgery. The Microsurgery Core will provide expertise and quality control from animal transplantation models for Projects 1, 2, and 3 of the program. The core unit will serve as a central resource to utilize the human and pig artery transplantation models in immunodeficient mouse chimeras that have been developed at Yale University. Double-mutant severe combined immunodeficient (SCID)/beige mice are grafted with human or pig arteries and are subsequently immunologically reconstituted with an adoptive transfer of human peripheral blood mononuclear cells (PBMC) and/or are treated with human or pig cytokines, such as the species-specific, T cell-derived factor, interferon-gamma (IFN-gamma). The interactions of the leukocytes or cytokines with the graft vascular cells results in immune-mediated arterial injury in a surrogate human experimental model. Project 1 will utilize the core unit to test the hypothesis that non-cytolytic IFN-gamma-secreting T cells can cause graft arteriosclerosis (GA) of human arteries in SCID/beige mice. Project 2 will utilize the core unit to determine the mechanisms by which IFN- gamma causes GA in human and pig arteries in immunodeficient mouse hosts. Project 3 will utilize the core unit to evaluate the utility of reagents reactive with IFN-gamma-producing mouse hosts. Project 3 will utilize the core unit to evaluate the utility of reagents reactive with IFN-gamma- producing T cells or with IFN-gamma-treated vascular cells to detect GA in human artery grafts in immunodeficient mice. Project 3 may also use a murine heterotopic cardiac allograft model for imaging studies.
The aims of the Microsurgery Core are: i) to provide the complex animal transplantation models to the program investigators using reliable materials and techniques; ii) to develop new methods for improving or adapting the in vivo models; and iii) to provide a collaborative small animal microsurgery training resource for investigators in vascular and transplantation biology. The methodology of the human PBMC- SCID/beige mouse artery transplantation model is relatively complex and requires shared facilities and special skills. The Microsurgery Core personnel have extensive with the required techniques and their combined expertise is essential to ensure consistency of the models and an economy of scale. By providing the artery xenograft model in SCID/beige mouse hosts to all of the projects, the Microsurgery Core will play a key role in this program.
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