Low-cost sequencing has ushered in a new era of drug discovery that can that utilizegenomic information from hundreds of thousands of people. However, humans are a limitedresource for identifying novel drug targets, and attempts at therapeutic development oftenrely on an already well-known set of genes and pathways. Greater potential for discovery existsif we broaden our search throughout the animal kingdom. In particular, animal adaptations fordisease resistance have great potential to unearth novel biological pathways to counteracthuman diseases. Hibernating mammals are an especially rich resource to inspire noveltherapeutics as they exhibit numerous transient phenotypes that mirror critical human healthproblems such as ischemia-reperfusion injury, Alzheimer's disease, osteoporosis, muscleatrophy, and obesity/diabetes, yet they are able to avoid or reverse pathologies. A systematicunderstanding of the gene networks utilized to generate the protective and healing phenotypesof hibernators has great potential to reveal novel therapeutic avenues; however, targets thatreproduce across independent datasets, including associating with the same phenotype acrossmultiple species have higher likelihood of translating to humans. In this proposal, we willvalidate targets identified in hibernators across other species. In order to obtain enough data forour phenotypes of interest, we have established a collaboration with the Monarch Initiative tocurate valuable phenotypes in currently underutilized species. While this proposal specificallyfocuses on identifying novel therapeutic targets for ischemia-reperfusion injury, our long-termvision is to develop a genomics discovery platform centered on hibernating animals forall of the diseases discussed above. We believe that our approach will identify noveltherapeutic targets that will translate to humans, and we will advance our findings with strategicpharmaceutical partners.
Project narrative: Genomic drug discovery leverages data from hundreds of thousands of people, but humans are a limited resource for identifying novel drug targets, and drug developers focus too often on well-known genes and pathways. Animal adaptations for disease resistance, particularly in hibernating mammals, have great potential to unearth novel biological pathways to counteract human diseases as they exhibit phenotypes that mirror diseases such as ischemia-reperfusion injury, Alzheimer's disease, osteoporosis, muscle atrophy, and obesity/diabetes but are able to avoid or reverse these pathologies. Here, we propose to analyze hibernation gene networks to identify new therapeutic targets and then validate these targets across multiple species. Alzheimer's Disease ; AD dementia ; Alzheimer ; Alzheimer Type Dementia ; Alzheimer disease ; Alzheimer sclerosis ; Alzheimer syndrome ; Alzheimer's ; Alzheimer's disease dementia ; Alzheimers Dementia ; Alzheimers disease ; Primary Senile Degenerative Dementia ; dementia of the Alzheimer type ; primary degenerative dementia ; senile dementia of the Alzheimer type ; Animals ; Ursidae Family ; Bears ; Ursidae ; bear ; Bile Acids ; Biological Assay ; Assay ; Bioassay ; Biologic Assays ; Biology ; Breeding ; Cell Line ; CellLine ; Strains Cell Lines ; cultured cell line ; Primary biliary cirrhosis ; Chronic Non-Suppurative Destructive Cholangitis ; Chronic Nonsuppurative Destructive Cholangitis ; Primary biliary cholangitis ; Diabetes Mellitus ; diabetes ; Disease ; Disorder ; Pharmaceutical Preparations ; Drugs ; Medication ; Pharmaceutic Preparations ; drug/agent ; Exhibits ; Genes ; Genotype ; Goals ; Health ; Heart ; Hibernation ; Human ; Modern Man ; In Vitro ; Ischemia ; Mammals ; Mammalia ; Methods ; Monsters ; Muscular Atrophy ; Muscle Atrophy ; muscle breakdown ; muscle degradation ; muscle deterioration ; muscle loss ; muscle wasting ; Obesity ; adiposity ; corpulence ; Osteoporosis ; Pathology ; Phenotype ; Rattus ; Common Rat Strains ; Rat ; Rats Mammals ; Reperfusion Therapy ; reperfusion ; Reperfusion Injury ; Ischemia-Reperfusion Injury ; Reperfusion Damage ; Research ; Resources ; Research Resources ; Saliva ; Spermophilus ; Citellus ; Suslik ; ground squirrel ; Testing ; Time ; Tissue Banks ; Tissue Collection ; Tissue repository ; Tissues ; Body Tissues ; Genetic Transcription ; Gene Transcription ; RNA Expression ; Transcription ; Translating ; Vision ; Sight ; visual function ; Data Set ; Dataset ; Myocardial Ischemia ; Ischemic Heart ; Ischemic Heart Disease ; Ischemic myocardium ; cardiac ischemia ; coronary ischemia ; heart ischemia ; myocardial ischemia/hypoxia ; myocardium ischemia ; base ; improved ; Biological ; Cardiac Myocytes ; Cardiac Muscle Cells ; Cardiocyte ; Heart Muscle Cells ; Heart myocyte ; cardiomyocyte ; Databases ; Data Bases ; data base ; Collaborations ; Therapeutic ; Knowledge ; programs ; interest ; human data ; success ; cohort ; Animal Models and Related Studies ; model of animal ; model organism ; Animal Model ; novel ; Modeling ; Genomics ; drug discovery ; resistance to disease ; resistant disease ; resistant to disease ; Disease Resistance ; Adenock ; Allo-Puren ; Allozym ; Allural ; Aloprim ; Alositol ; Anoprolin ; Anzief ; Apulonga ; Apurin ; Apurol ; Bleminol ; Bloxanth ; Caplenal ; Cellidrin ; Cosuric ; Dabroson ; Embarin ; Epidropal ; Foligan ; Geapur ; Gichtex ; Hamarin ; Hexanurat ; Ketanrift ; Ketobun-A ; Ledopur ; Lopurin ; Lysuron ; Miniplanor ; Monarch ; Nektrohan ; Pan Quimica ; Remid ; Riball ; Suspendol ; Takanarumin ; Urbol ; Uricemil ; Uripurinol ; Urosin ; Urtias ; Xanturat ; Zyloprim ; Zyloric ; Aloral ; Pharmaceutical Agent ; Pharmaceuticals ; Pharmacological Substance ; Pharmacologic Substance ; Address ; Data ; Research Contracts ; in vitro Model ; in vivo ; in vivo Model ; Ontology ; Validation ; Cellular Morphology ; cell morphology ; Pathway interactions ; pathway ; cost ; healing ; knock-down ; knockdown ; design ; designing ; protective effect ; interoperability ; human disease ; novel therapeutics ; new drug treatments ; new drugs ; new therapeutics ; new therapy ; next generation therapeutics ; novel drug treatments ; novel drugs ; novel therapy ; therapeutic development ; therapeutic agent development ; overexpression ; overexpress ; new therapeutic target ; new drug target ; new druggable target ; new pharmacotherapy target ; new therapy target ; novel drug target ; novel druggable target ; novel pharmacotherapy target ; novel therapeutic target ; novel therapy target ; transcriptome sequencing ; RNA Seq ; RNA sequencing ; RNAseq ; screening ; reference genome ; reference assembly ; experimental study ; experiment ; experimental research ; bioinformatics resource ; bio-informatics resource ; cardioprotection ; cardioprotectant ; cardioprotective ; heart damage ; cardiac damage ; knowledge graph ; graph knowledge base ; graph knowledgebase ;
