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We are currently funded by NIH to create monkey models for
three human neurogenetic diseases: Ataxia-Telangiectasia (A-T), Kallmann’s
syndrome and Lesch-Nyhan’s disease. In A-T, the Purkinje cells of the
cerebellum begin degenerating shortly after birth resulting in a progressive
ataxia. These patients are also at increased risk of cancer and immune
system dysfunction. In Kallmann's syndrome, patients are anosmic and
hypogonadal. The olfactory nerve and luteinizing hormone-releasing hormone
neurons do not enter the brain in this disease. In
Lesch-Nyhan’s disease, children suffer from mental retardation and
self-mutilation.
The production of gentically modified primates requires new technology. Our
approach is to extend the lifespan of somatic cells by transfecting them
with the reverse transcriptase component of telomerase. We then use gene
targeting technology to disrupt the genes we are interested in. We
collaborate with investigators proficient in nuclear transfer (whole animal
cloning). They will transfer the nucleus of the cell that we genetically
modify into enucleated oocytes. The resulting reprogrammed cell will
develop into an embryo which can be transferred to a host mother. Once the
animals are born, they will be used to understand the mechanisms responsible
for the symptoms observed in humans and to test different therapeutic
approaches.
Nonhuman primates (NHPs) are essential for biomedical research due to their
similarities to humans. The utility of NHPs will be greatly increased by the
application of genomicsbased approaches such as gene expression profiling.
Sequence information from the 3' end of genes is the key resource needed to
create oligonucleotide expression arrays. We developed the algorithms and
procedures necessary to quickly acquire sequence information from the 3' end
of nonhuman primate orthologs of human genes. To accomplish this, we
identified terminal exons of over 15,000 human genes by aligning mRNA
sequences with genomic sequence. We designed primers to amplify genomic DNA,
which included at least 300 bp of the terminal exon. We cloned and sequenced
the PCR products representing over 5,500 Macaca mulatta (rhesus monkey)
orthologs of human genes. This sequence information has been used to select
probes for rhesus gene expression profiling. Affymetrix and Agilent used
sequences obtained with this approach in the design of their rhesus macaque
oligonucleotide microarrays.
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