Project Summary/Abstract:
Low-cost sequencing has ushered in a new era of drug discovery that can that utilize
genomic information from hundreds of thousands of people. However, humans are a limited
resource for identifying novel drug targets, and attempts at therapeutic development often
rely on an already well-known set of genes and pathways. Greater potential for discovery exists
if we broaden our search throughout the animal kingdom. In particular, animal adaptations for
disease resistance have great potential to unearth novel biological pathways to counteract
human diseases. Hibernating mammals are an especially rich resource to inspire novel
therapeutics as they exhibit numerous transient phenotypes that mirror critical human health
problems such as ischemia-reperfusion injury, Alzheimer’s disease, osteoporosis, muscle
atrophy, and obesity/diabetes, yet they are able to avoid or reverse pathologies. A systematic
understanding of the gene networks utilized to generate the protective and healing phenotypes
of hibernators has great potential to reveal novel therapeutic avenues; however, targets that
reproduce across independent datasets, including associating with the same phenotype across
multiple species have higher likelihood of translating to humans. In this proposal, we will
validate targets identified in hibernators across other species. In order to obtain enough data for
our phenotypes of interest, we have established a collaboration with the Monarch Initiative to
curate valuable phenotypes in currently underutilized species. While this proposal specifically
focuses on identifying novel therapeutic targets for ischemia-reperfusion injury, our long-term
vision is to develop a genomics discovery platform centered on hibernating animals for
all of the diseases discussed above. We believe that our approach will identify novel
therapeutic targets that will translate to humans, and we will advance our findings with strategic
pharmaceutical partners.