Public Health Interests
Evolution; Temperature regulation
Cellular & Molecular Physiology: Bagriantsev & Gracheva Labs
Extensive Research Description
My lab is interested in somatosensation and thermoregulation, particularly molecular and evolutionary mechanisms whereby the somatosensory and thermoregulatory systems adapt to the environmental and behavioral needs of an organism. We intend:
(i) To understand, which molecules mediate different types of sensation undernormal and extreme physiological conditions using mammalian hibernation as a naturally reversible model.
(ii) To dissect lecmoular mechanism(s) of thermoregulation and thermogenesis using hibernators in their active and torpor physiological states.
Animals that tune their temperature sensitivity to the extreme provide unique model systems for dissecting molecular mechanism(s) by which thermosensory pathways adapt to environmental conditions. Mammalian hibernation is fascinating as it is characterized by prolonged alternating periods of hypothermia (core body temperature drops from 37°C to 2-10°C) in association with unusual resistance of tissues to cold. Despite the robustness of these phenomena, fundamental questions remain about their cellular basis. Mammalian hibernators (thirteen-lined ground squirrels and Syrian hamsters) provide unique natural system for understanding thermotransduction machinery. Moreover, comparisons between phylogenetically related species of hibernators and non-hibernators will provide insights into anatomical, physiological, and genetic factors that support this unique thermo-adaptive process. Due to the complexity and dynamic nature of thesomatosensory and thermoregulatory systems, we are taking an integrated approach using biochemistry, bioinformatics, live-cell imaging, electrophysiology, genomics, behavioral paradigms, and additional cellular and molecular biological techniques to approach these fascinating questions of both physiological and clinical significance.
Mechanisms gleaned from this study could have profound outcomes for human health in regard to:
(i) Inducible and reversible hypothermia. Induced hypothermia is widely used during brain injury, trauma, cardiac arrest and ischemia; however the window for dropping of body core temperature is very narrow, from ~37°C to ~33°C. Understanding the molecular basis for regulated and reversible hypothermia of hibernators can help to improve survival during extreme conditions and expand the window for cooling of human core body temperature.
(ii) Cold tolerance and hypersensitivity. Indeed, such conditions are common hallmarks of chemotherapy- and nerve injury-induced neuropathic pain, in which even mild cool stimuli can be perceived as excruciatingly painful - a phenomenon generally referred to as cold allodynia.
(iii) Tissue transplantation. Hypothermic preservation of organ for transplantation is another important biomedical challenge. Despite huge progress in this area of research, there are still numerous hurdles associated with extended cold storage of organs. Multiple studies suggest that tissues from hibernators in torpor state are more tolerant to hypothermic storage compared to those from hibernators in the active state, or from non-hibernating animals, such as rats and rabbits. Therefore, mammalian hibernators represent a superb model for understanding evolutionary and functional mechanisms that support cold tolerance.
Neuronal UCP1 expression suggests a mechanism for local thermogenesis during torpor.
Laursen WJ, Mastrotto M, Pesta D, Funk O, Goodman J, Merriman D, Ingolia N, Shulman G, Bagriantsev SN, Gracheva EO. PNAS 2015, 111(5):1607-12.
Ganglion-specific splicing of TRPV1 underlies infrared sensation in vampire bats.
Gracheva EO, Cordero-Morales JF, González JA, Ingolia NT, Aranguren CI, Manno C, Weissman JS, Julius D. (2011)
Molecular basis of infrared detection by snakes.
Gracheva EO, Ingolia NT, Kelly YM, Cordero-Morales JF, Hollopeter G, Chesler AT, Sánchez EE, Perez JC, Weissman JS, Julius D. Nature (Article) 2010; 464(7291):1006-11 PMID: 20228791. Evaluated by The Faculty of 1000.
Cytoplasmic ankyrin repeat domains of TRPA1 dictate sensitivity to thermal and chemical stimuli.
Cordero-Morales JF, Gracheva EO, Julius D. PNAS 2011, PMID: 21930928.
Tomosyn negatively regulates CAPS-dependent peptide release at Caenorhabditis elegans synapses.
Gracheva EO, Burdina AO, Touroutine D, Richmond JE. J Neurosci. 2007, 27(38):10176-10184 PMID: 17881523
Tomosyn inhibits Synaptic Vesicle Priming in Caenorhabditis elegans. PLoS Biology.
Gracheva EO, Burdina AO, Holgado AM, Berthelot-Grosjean M, Hadwiger G, Nonet ML, Weimer RM, Richmond JE. 2006, 4(8). PMID: 16895441. Evaluated by The Faculty of 1000.