The ultimate objective of this proposal is to relieve the organ shortage crisis by genetic alteration of pigs so porcine tissues and organs can be transplanted to humans (i.e. xenotransplantation) with results equivalent to those attainable with allografts under conventional immunosuppression. Progress toward this objective has been precluded by the innate immune reaction of higher primate recipients that targets the alphaGal epitopes that are expressed on the surface of pig but not human cells. Having characterized the full genomic organization and transcriptional regulation of the alphaGT gene in several lower mammals (including pigs) and in all of the higher mammals (including humans), we are collaborating with PPL Therapeutics in their efforts to generate for the first time recombinant pig cells that have double alpha1,3GT allele knockout (KO). These double KO cells can be used for somatic cell nuclear transfer (cloning) to produce cloned double KO fetuses and piglets. We intend to fully characterize the molecular alterations and phenotypic qualities of the recombinant fetal cells, as well as the cells, tissues, or organs of the anticipated full-term cloned piglets. In addition, the double KO fetal cells, and the cells, tissues, and organs of these piglets will be tested in transgenic mouse models that will allow prediction of the innate and adaptive immune responses generated by alphaGal-negative higher primate recipients (including humans) to the genetically altered porcine xenografts.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK064207-03
Application #
6884683
Study Section
Immunobiology Study Section (IMB)
Program Officer
Doo, Edward
Project Start
2003-06-01
Project End
2007-03-31
Budget Start
2005-04-01
Budget End
2007-03-31
Support Year
3
Fiscal Year
2005
Total Cost
$254,198
Indirect Cost
Name
University of Pittsburgh
Department
Surgery
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
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