Acute and chronic pain represent significant and under-treated health problems in the U.S. due, in part, to our incomplete understanding of the mechanisms by which the peripheral nervous system detects noxious stimuli. TRPV1 is a heat-gated ion channel required for some, but not all aspects of heat-evoked pain. Three related channels, TRPV2, TRPV3, and TRPV4, can also be activated by elevated temperatures and therefore may contribute to the detection of painful heat. TRPV2 is activated at very high temperatures (>52 degrees C) and expressed most highly in a subset of sensory neurons. TRPV3 and TRPV4 are activated at temperatures >32 degrees C. In the skin, TRPV3 and TRPV4 expression is most prominent in epithelial keratinocytes, raising the possibility that these cells participate in an indirect mode of thermosensation involving TRPV3 and TRPV4. TRPV2 and TRPV4 can also be activated by cell swelling, suggesting that they may participate in mechanosensation. This proposal is aimed at achieving the following goals: (1) To determine whether and how TRPV2 and TRPV4 contribute to the detection of painful and nonpainful thermal and mechanical stimuli. (2) To determine whether keratinocyte TRPV3 and TRPV4 contribute to noxious and/or innocuous thermosensation and mechanosensation. (3) To determine how keratinocytes communicate the presence of thermal stimuli to adjacent sensory neurons. To achieve these goals, TRPV2 and TRPV4 null mutant mice will be analyzed for acute responsiveness to mechanical and thermal stimuli and for enhancement of thermo- or mechanosensitivity following inflammation or nerve injury. Wild-type or dominant negative forms of TRPV3 or TRPV4 will be overexpressed selectively in keratinocytes and the effects on thermosensation evaluated behaviorally. Finally, biochemical electrophysiological, fluorescent calcium imaging, and behavioral methods will be used to identify molecules through which heat-exposed keratinocytes communicate with nearby sensory neurons.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS051551-01
Application #
6911863
Study Section
Somatosensory and Chemosensory Systems Study Section (SCS)
Program Officer
Porter, Linda L
Project Start
2005-06-01
Project End
2010-05-31
Budget Start
2005-06-01
Budget End
2006-05-31
Support Year
1
Fiscal Year
2005
Total Cost
$338,984
Indirect Cost
Name
Johns Hopkins University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
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