Peripheral sensitization is a process by which pain fibers become sensitized to innocuous stimuli (allodynia) or more sensitive to noxious stimuli (hyperalgesia). This process occurs through a variety of inflammatory mediators and signaling pathways, with downstream targets including several receptors important for signal transduction. Transient receptor potential vanilloid 1 (TRPV1) is an important non-selective cation channel and receptor in this process. It is sensitive to heat, acid, and vanilloids, includig the 'hot'component of chili peppers, capsaicin. Several inflammatory compounds and pathways can affect its sensitivity to its known ligands. To date, most studies have focused on the individual compounds and the pathways by which they affect TRPV1. This study aims to show that TRPV1 sensitization can be more accurately modeled by using a multi-pronged sensitization approach. Through in vitro calcium-based imaging and electrophysiological techniques, we will explore the characteristics of TRPV1 sensitization including characteristics of particular neuronal sub-populations within dorsal root and trigeminal ganglia. Short- and long-term models will be used to assess these differences and then applied as systems for screening therapeutics. We will begin with compounds that are known to block important signaling molecules such as PKA, PKC, PI3K, and p38 MAPK with the objective of finding key pathways important for TRPV1 sensitization. Finally, high throughput identification screen data will be applied to this model to more closely mimic the inflammatory milieu in vitro and show novel TRPV1-modifying inflammatory compounds.

Public Health Relevance

Transient receptor potential vanilloid 1 (TRPV1) is an important sensor throughout the body that responds to heat, acid, and other chemical compounds, including the 'hot'ingredient of chili peppers. Inflammatory compounds can modify TRPV1 to become even more sensitive, leading to more pain. This project aims to better understand the modification of TRPV1 by inflammation to develop better analgesic options.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
Project #
5F30DE023033-02
Application #
8531679
Study Section
NIDCR Special Grants Review Committee (DSR)
Program Officer
Frieden, Leslie A
Project Start
2012-07-01
Project End
2017-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
2
Fiscal Year
2013
Total Cost
$28,473
Indirect Cost
Name
Harvard University
Department
Dentistry
Type
Schools of Dentistry
DUNS #
047006379
City
Boston
State
MA
Country
United States
Zip Code
02115