This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. X-linked severe combined immunodeficiency is a lethal disorder in which affected children succumb early in life to infection. We had previously identified a canine model of this disorder in the Basset Hound, and developed a colony in which it was shown that the clinical, pathologic, and immunologic as well as genetic (X-linked) characteristics of the canine disease are essentially identical to those in humans. The colony was subsequently transferred to Dr. Peter Felsburg for further immunologic studies at the University of Illinois and Purdue University. Dr. Felsburg returned to the University of Pennsylvania in 1992 and joined the Referral Center, to define the molecular defect in this disorder. While the colony was supported primarily by Dr. Felsburg's grants, the Referral Center grant provided some technical assistance, as well as support for working out the molecular genetics of the canine model. In 1994, Dr. Henthorn of the Referral Center cloned the Basset XSCID gene, showing that it is the same gene as reported to be defective in human XSCID. The gene encodes the gamma subunit common to several interleukins, which play an important role in the proliferation and function of T cells of the immune system. Subsequently, Dr. Henthorn, in the Molecular Genetics Lab of the Referral Center identified XSCID in a family of Cardigan Welsh Corgis with a 1 base pair deletion in the common gamma chain 5' coding sequence. A small breeding colony of Welsh Corgi XSCID, consisting of carrier females and bone marrow transplanted XSCID males, is currently being maintained by one of Dr. Felsburg s NIH grants. These colonies are currently funded to: (1) Develop and evaluate strategies for improving hematopoietic stem cell transplantation for XSCID; (2) Develop and evaluate strategies for treating XSCID with gene therapy and to evaluate the potential long-term side effects of gene therapy; and (3) Evaluate the role of the common gamma chain in tissues other than of lymphoid origin.
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