DESCRIPTION (provided by applicant): We depend on the sense of touch for most individual and social activities. Many forms of injuries and inflammation are accompanied by allodynia and mechanical hyperalgesia, conditions in which innocuous touch stimuli now cause severe pain. Despite its fundamental importance, mechanotransduction remains one of the least understood signaling process, both at the cellular and molecular levels. Touch is transduced by specialized mechanosensors embedded in the skin, most of which are composed of nerve endings and associated glial and epithelial cells. The role of these non-neuronal cells in touch sensation is poorly understood. Our goal is to understand touch sensation by dissecting functional interactions between mechanosensory neurons and glia using genetic, molecular and physiological strategies in C. elegans. Specifically, I hypothesize that such interactions employ the ion channel DELM-1, a member of the DEG/ENaC family of cationic channels, expressed in mechanosensory glia. Based on our preliminary results and what is known about the role of DEG/ENaC channels in epithelia, I hypothesize that glial DELM-1 is needed to control the concentration of K+ in the microenvironment between the neuronal ending and glia. Pilot experiments suggest that DELM-1 is inhibited by mechanical forces. Thus, I also hypothesize that the control of extracellular K+ by DELM-1 is highly dynamic and contributes to adaptation of the mechanosensors. The aims of this proposal are: 1) Does the glial DELM-1 channel regulate the activity of mechanosensory neurons? 2) Does DELM-1 elevate [K+] in the microenvironment between glia and touch neurons? 3) Is the glial DELM-1 channel mechanosensitive? Beautiful work in mammalian tissues using skin-nerve preparation and Von-Frey hair has allowed major progress in our understanding of touch sensation. I have now the unprecedented opportunity to capitalize on this previous work to explore a new area in the field. My work is likely to be relevant to our understanding of how associated cells, including glia, control the function of neurons throughout the nervous system. PUBLIC HEALTH RELEVANCE: Without the sense of touch we could not feed ourselves, hold objects, move around and care for our offspring. In many forms of injury and inflammation touch stimuli become painful. Touch is mediated by activation of receptors in the skin, most of which are composed of nerve cells and associated cells. The role of these associated cells in touch sensation is largely unknown. I propose here to advance our understanding of the functional interaction between nerve and associated cells in touch sensation using the tractable model system C. elegans. My work will ultimately help elucidate how cells associated with nerve cells contribute to sensory neuropathy and other human neurological disorders.
|Effective start/end date||2/1/11 → 11/30/16|
- National Institutes of Health: $334,688.00
- National Institutes of Health: $322,974.00
- National Institutes of Health: $332,601.00
- National Institutes of Health: $331,341.00
- National Institutes of Health: $320,775.00