Hibernating mammals have evolved to be able to endure extreme stress, sub-zero temperatures and lack of food for up to 75% of the year. Understanding the genes and pathways involved in these adaptations would allow these mechanisms to be translated into human therapies. However, the key animal model for hibernation, the 13-lined ground squirrel, has yet to be fully developed. The lack of a centralized platform is one major obstacle preventing gene-based rational drug design from the protective effects of hibernation. In this proposal, we will build a multi-omics hibernation discovery platform for the 13-lined ground squirrel by integrating genomic, transcriptomic, proteomic and evolutionary analyses to generate novel drug targets. As part of this work, we will produce the first ATAC-seq study performed in a hibernating mammal, a key component of integrating genomic and transcriptomic data, as well as building networks to predict the function and regulation of predicted targets. We will additionally perform in-vitroâ validation of the predicted drug targets from our integrated analyses. By developing a discovery platform for a model hibernator, the 13-lined ground squirrel, and demonstrating its utility, we will enable therapeutic discovery for diseases with large clinical needs like heart disease, stroke, Alzheimerâs, Type II Diabetes, and sarcopenia. This study is of interest to several NIH institutes (NIDDK, NHLBI, NINDS and NIAMS).
Public Health Relevance Statement: Project Narrative Hibernating mammals represent an untapped resource for novel therapeutics development across many clinical indications including heart attack, stroke, and diabetes. Here, we propose to create an integrated computational platform for drug discovery using the hibernating 13-lined ground squirrel and perform functional validation of the identified therapeutics. This work will be used to support drug development efforts relevant to multiple NIH institutes.
NIH Spending Category: Aging; Basic Behavioral and Social Science; Behavioral and Social Science; Biotechnology; Cardiovascular; Genetics; Heart Disease; Human Genome; Neurosciences
Project Terms: Alzheimer's Disease; Animal Model; Anti-inflammatory; ATAC-seq; Atrophic; Autophagocytosis; Awareness; base; biobank; Biology; bone; Candidate Disease Gene; Cell Line; Chromatin; Clinical; computational platform; Computer Simulation; Contracts; Data; Data Set; Diabetes Mellitus; Disease; Drug Design; drug development; drug discovery; Drug Screening; Drug Targeting; Epigenetic Process; follow-up; Food; Future; Generations; Genes; Genomics; Goals; Health; Heart; Heart Arrest; Heart Diseases; Heart Rate; Hibernation; Hour; Human; human disease; Hypothalamic structure; In Vitro; in vivo; Individual; Inflammatory Response; inhibitor/antagonist; Institutes; Insulin Resistance; interest; Ischemia; Knowledge; Mammals; Mediating; metabolic rate; Metabolic syndrome; Mission; Modeling; multiple omics; Muscle; Muscular Atrophy; Myocardial Infarction; NAPVSIPQ peptide; National Heart, Lung, and Blood Institute; National Institute of Arthritis and Musculoskeletal and Skin Diseases; National Institute of Diabetes and Digestive and Kidney Diseases; National Institute of Neurological Disorders and Stroke; Neurons; new therapeutic target; Non-Insulin-Dependent Diabetes Mellitus; novel; novel therapeutics; Obesity; Organ Transplantation; Pathway Analysis; Pathway interactions; Pattern; Pharmaceutical Preparations; Pharmacologic Substance; Phenotype; Physiological Processes; predictive test; prevent; protective effect; Proteomics; reference genome; Regulation; Reperfusion Injury; Reperfusion Therapy; repository; Resources; sarcopenia; small molecule; Spermophilus; Stress; Stroke; stroke recovery; Temperature; Testing; Therapeutic; therapeutic candidate; therapeutic development; Time; Tissues; transcription factor; transcriptomics; Translating; Traumatic injury; United States National Institutes of Health; Validation; W
