Grant: $560,303 - National Institutes of Health - Sep. 11, 2009
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Award Description: Chemical and thermal pain in the cornea is primarily transduced by a calcium- and sodium-permeable ion channel called TRPV1 expressed in nociceptors with cell bodies in the trigeminal ganglia. When injury (including surgery) or illness cause inflammation, the inflammatory process increases the sensitivity of TRPV1 ion channels to painful stimuli, a phenomenon known as inflammatory hyperalgesia. Our long-term goal is to understand the molecular mechanisms mediating inflammatory hyperalgesia, a critical first step in developing more effective pain therapies for corneal injury. In this study, we will focus on the molecular mechanisms of TRPV1 modulation by Nerve Growth Factor (NGF). Inflammation and injury lead to release of trophic factors such as NGF, insulin, and Insulin-like Growth Factor, which increase nociceptor excitability by activating receptor tyrosine kinases (RTKs). It has been proposed that RTK activation sensitizes TRPV1 through hydrolysis of phosphoinositide 4,5-bisphosphate (PIP2), relieving a tonic inhibition of TRPV1 by PIP2. The role of PIP2 is controversial, however, due to emerging evidence that phosphoinositide 3,4,5-trisphosphate (PIP3) may be involved. Based on our preliminary data, we propose that phosphorylation of PIP2 by phosphoinositide 3-kinase (PI3K) to form PIP3 may be an essential element of nociceptor sensitization by NGF. Our specific aims will address the molecular mechanism and functional significance of TRPV1 modulation by NGF. Understanding the regulation of TRPV1 by RTKs is critical to a complete understanding of how inflammation modulates corneal nociceptor excitability and to the development of improved therapies to treat inflammatory pain.
Project Description: We received notice of funding less than two weeks ago. We excited to begin this new accelerated phase of our research.
Jobs Summary: Not Applicable this Quarter (Total jobs reported: 0)
Project Status: Not Started
This award's data was last updated on Sep. 11, 2009. Help expand these official descriptions using the wiki below.