Nociception, the process through which a subset of sensory neurons detects noxious (painful) stimuli, is an important but poorly understood process in the trigeminal ganglion neurons that innervate the cornea. These neurons respond to a wide array of irritating stimuli including heat, cooling, mechanical force, and chemicals including protons and inflammatory molecules. Inflammation in the cornea, a result of damage to the neurons that innervate it, often leads to sensitization of those neurons. The response to noxious stimuli and to inflammatory molecules is mediated in large part by ion channels, G-protein coupled receptors (GPCRs), and receptor tyrosine kinases (RTKs). A better understanding of the ion channels involved in ocular pain and the hyperalgesic sensory pathway would be important for development of more targeted pain management tools. The goal of this work is to understand the cellular and molecular mechanisms by which GPCRs and RTKs regulate the function, trafficking, and expression of ion channels during pain transduction. To do this, I will use acid-sensing ion channels (ASICs) as a model system because they have been shown to mediate pain in response to tissue acidification and they are regulated during inflammation in cutaneous sensory neurons. These important channels for pain sensation are poorly studied in the cornea despite the fact that corneal neurons display a strong response to changes in pH. In this proposal, I plan to identify the proteins responsible for detection of acidic pH in corneal neurons. To do this I will learn to record directly from corneal nerve terminals. In addition, I wil examine the effects of pro-inflammatory molecules like kinins and prostaglandins of the acid-sensitive currents. Many of these inflammatory molecules trigger the activation of the phospholipase c signaling pathway, which reduces the amount of the phosphoinositide, PI(4,5)P2, in the membrane. Thus, I will examine the role phosphoinositides play in corneal neurons and in the regulation of ASICs.

Public Health Relevance

Little is understood about ocular pain, which can include pain at the ocular surface, orbital pain, and referred pain. This proposal will strive to discover the molecules responsible for sensing the pain associated with acidosis and how those molecules are regulated during inflammation.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Career Transition Award (K99)
Project #
1K99EY024267-01
Application #
8676511
Study Section
Special Emphasis Panel (ZEY1-VSN (02))
Program Officer
Agarwal, Neeraj
Project Start
2014-09-01
Project End
2016-08-31
Budget Start
2014-09-01
Budget End
2015-08-31
Support Year
1
Fiscal Year
2014
Total Cost
$90,355
Indirect Cost
$6,693
Name
University of Washington
Department
Physiology
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195