This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. The long-term goal of this proposal is to expand and study our colony of nonhuman primates affected with Globoid Cell Leukodystrophy (GLD;Krabbe's disease). This colony of rhesus monkeys represents the only colony of nonhuman primates in the world in which an inherited lysosomal disorder has been recognized, propagated, and is available for study. The primary focus of this R24 grant is to markedly improving the efficiency of producing macaques affected with GLD through a stringent natural breeding program. There are 13 established harem breeding groups containing a carrier male and a combination of carrier and normal females. These social groups have been created based on pedigree data from the carrier colony as well as the availability of normal females who could be placed with carrier males. Of the 21 known pregnancies, there were 21 live births (2 affected, 10 carrier, 8 normal, 1 genetic status to be determined [either normal or carrier]). We continue to characterize disease pathogenesis and generate a database with the affected animals through molecular, biochemical, clinical, behavioral, and pathologic analyses to develop an extensive baseline of knowledge of disease progression in the nonhuman primate model. The 2009 affected infants died at 160 days and 242 days. As an effective alternative to whole animal studies, we have initiated a cell and tissue banking program for the GLD animals. The primary goal for this program is to make viable cells (peripheral blood and bone marrow mononuclear cells, mesenchymal stem cells, and skin fibroblasts) and tissue samples (primary organ systems) available to investigators for their research. As of February 2010, there are 75 total animals in the colony, 48 heterozygous (carrier) animals: 30 breeding age animals (16 males and 14 females), 5 juveniles (4 males and 1 female), and 13 infants/yearlings (7 males, 6 females). Currently the Krabbe Breeding Colony is a conventional colony (i.e., animals are positive for B virus and/or STLV-1). As TNPRC has made it a priority to phase out conventional colonies, plans have been made to derive Krabbe carriers and convert this special colony to one with animals that are negative for the four target viruses (B virus, STLV-1, SIV, SRV). TNPRC has had great success in establishing three different SPF colonies;therefore, the SPF Krabbe colony will be established using the same paradigm. Briefly, carrier offspring between 8-months to 1-year of age will be removed from their conventional natal group and placed in small runs or corncribs with other animals being similarly derived. They will spend the next 2 years in small peer groups and be viral tested 4x/year. After the first 2 years of testing is completed, carrier x carrier and carrier x normal breeding groups will be established with viral testing occurring 2x/year. If an animal tests B+ or STLV+, it will be returned to its natal group or placed with other animals with similar testing results. Because of their genetic value as carriers, they will be maintained for breeding with animals having similar test results. As of April 2010, six carrier infants have entered the process.
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