Mammals that hibernate depress their metabolic, heart and respiratory rates, as well as their core body temperature (Tb) to enter a state called torpor. In hibernators such as ground squirrels, torpor is precisely controlled and fully reversible using only endogenous mechanisms, yet relatively little is known about the molecular events that underlie hibernation's critical transitions. Understanding the biochemical aspects well enough to recapitulate them in a non-hibernator has profound implications for human health, offering an unprecedented opportunity to improve outcomes for victims of cardiac arrest, stroke, trauma, and hypothermia, as well as in organ transplant and routine surgery. Hibernation is an adaptive strategy for energy conservation that is exploited by many distantly related mammals;this broad phylogenetic distribution argues strongly that genetic capability underlying the phenotype is shared among mammals. Thus, we predict that an understanding of natural mammalian hibernation will lead to rational development of safe hypometabolic and protective strategies for human applications. Here we propose that hibernation comprises two biochemical switches: the first switch is a summer-to-winter switch that resets gene expression in a number of pathways leading to a protected phenotype. The second switch is a torpor-to-arousal switch that creates the heterothermic pattern characteristic to the hibernating phenotype and is responsible for reversible metabolic suppression. Markers associated with these two switches will be identified using proteomic and metabolomic techniques. The success of this work critically depends upon a carefully collected set of samples based upon the natural rhythms associated with the two switches. 21 sample groups from 13-lined ground squirrels will be analyzed, 9 for the summer-to-winter switch and 12 for the torpor-to-arousal switch. Initial focus will be on plasma, heart, lung, liver and brain, but other tissues will be collected to make a tissue bank of these valuable timepoints for additional studies and for use by the hibernation research community. Identification of these markers increases understanding of mammalian hibernation, and provides significant novel insights into natural mechanisms that achieve metabolic suppression and protection from ischemia/reperfusion injury in mammals. These markers offer an untapped source for discovery of new targets for therapeutic intervention in heart, lung and blood diseases in humans.

Public Health Relevance

Mammalian hibernation is a natural example of molecular and cellular adaptation to extreme environmental conditions;hibernators repeatedly cycle through periods of limited oxygen delivery and low body temperatures that would inevitably evoke life‐threatening cardiovascular and respiratory responses in humans. The understanding of the endogenous molecular mechanisms that permit these mammals to survive such physiological extremes offers untapped potential to discover drug targets and therapeutic interventions for the treatment and prevention of heart, blood, and lung diseases, as well as sleep and circadian rhythm disorders.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL089049-04
Application #
8022882
Study Section
Special Emphasis Panel (ZRG1-CVS-A (50))
Program Officer
Wong, Renee P
Project Start
2008-03-15
Project End
2014-02-28
Budget Start
2011-03-01
Budget End
2014-02-28
Support Year
4
Fiscal Year
2011
Total Cost
$373,672
Indirect Cost
Name
University of Colorado Denver
Department
Biology
Type
Schools of Medicine
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
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Hindle, Allyson G; Otis, Jessica P; Epperson, L Elaine et al. (2015) Prioritization of skeletal muscle growth for emergence from hibernation. J Exp Biol 218:276-84
Hindle, Allyson G; Grabek, Katharine R; Epperson, L Elaine et al. (2014) Metabolic changes associated with the long winter fast dominate the liver proteome in 13-lined ground squirrels. Physiol Genomics 46:348-61
Hindle, Allyson G; Martin, Sandra L (2013) Cytoskeletal regulation dominates temperature-sensitive proteomic changes of hibernation in forebrain of 13-lined ground squirrels. PLoS One 8:e71627
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Jani, Alkesh; Orlicky, David J; Karimpour-Fard, Anis et al. (2012) Kidney proteome changes provide evidence for a dynamic metabolism and regional redistribution of plasma proteins during torpor-arousal cycles of hibernation. Physiol Genomics 44:717-27
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Epperson, L Elaine; Karimpour-Fard, Anis; Hunter, Lawrence E et al. (2011) Metabolic cycles in a circannual hibernator. Physiol Genomics 43:799-807
Grabek, Katharine R; Karimpour-Fard, Anis; Epperson, L Elaine et al. (2011) Multistate proteomics analysis reveals novel strategies used by a hibernator to precondition the heart and conserve ATP for winter heterothermy. Physiol Genomics 43:1263-75

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