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Molecular, cellular, anatomical and neurobiological investigation of melanopsin-expressing corneal innervation, and its role in pain and photophobia

Award Number: R01EY030864
ORGANIZATION: NATIONAL EYE INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Project Summary/Abstract: Corneal pain is an important mechanism to detect injury or damage, leading to protective responses to limit injury if possible (tearing to remove a foreign object), initiate healing and protect the ocular surface required for clear vision. When maladaptive, corneal pain can be so debilitating as to limit daily function, dramatically reduce quality of life, and cause significant economic burden. There is considerable understanding of the molecular and cellular underpinnings of pain perception in response to mechanical, chemical and thermal stimuli, but the ability of light to influence pain (photoallodynia) after corneal injury is not well understood. Accumulating evidence suggests photoallodynia uses melanopsin-expressing trigeminal ganglia sensory neurons in addition to the classic retinal pathways, and that these same trigeminal ganglia neurons contribute to corneal mechanical sensitivity. In this proposal, the knowledge gap concerning how this class of trigeminal neurons contribute to corneal pain in normal and sensitized pathophysiological states in disease models of corneal surface injury/dry eye disease, allergic eye disease and migraine will be addressed. Preliminary data shows that melanopsin is expressed in both C-fiber (thermal and chemical) and Ad (pressure) sensing mouse and human trigeminal neurons, some of which co-express CGRP. These melanopsin- expressing neurons contribute to corneal mechanical and light sensitivity in normal and pathophysiological conditions, and can respond to light ex vivo. Finally, the optic nerve is not required for behavioral measures of light sensitivity in a model of trigeminal sensitization. Thus the hypothesis that melanopsin-containing corneal trigeminal neurons function to modulate corneal mechanical sensitivity and light sensitivity by directly contributing to corneal innervation, and use neuropeptides to modulate the corneal milieu to effect pain perception and sensitization will be tested. Aim 1 will evaluate corneal innervation in adult and developmental stages in mice lacking melanopsin-expressing trigeminal neurons to identify the mechanism by which these mice have decreased corneal mechanical sensitivity. Aim 2 will evaluate the ability of melanopsin-expressing corneal nerves to alter mechanical and light sensitivity by altering secretion of a representative neuropeptide in normal and sensitized corneas in response to light. Aim 3 will evaluate which trigeminal ganglia neurons (C- fiber of Ad) contribute to mechanical and light sensitivity in models of corneal disease, injury or sensitization. The expected outcomes will elucidate molecular, cellular, anatomical and neurobiological mechanisms of corneal innervation, pain and photoallodynia in normal and pathophysiological states.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2024 ( Subtotal = $390,000 )
2024	2024	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Vision Research	000	5	12/8/2023	NON-COMPETING CONTINUATION	$390,000
														Subtotal = $390,000

Issue Date FY: 2023 ( Subtotal = $390,000 )
2023	2023	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Vision Research	000	4	1/5/2023	NON-COMPETING CONTINUATION	$351,000
2023	2023	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Vision Research	001	4	3/8/2023	NON-COMPETING CONTINUATION	$39,000
														Subtotal = $390,000

Issue Date FY: 2022 ( Subtotal = $378,300 )
2022	2022	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Vision Research	000	3	1/31/2022	NON-COMPETING CONTINUATION	$378,300
														Subtotal = $378,300

Issue Date FY: 2021 ( Subtotal = $378,300 )
2021	2021	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90095	LOS ANGELES	USA	Vision Research	000	2	12/10/2020	NON-COMPETING CONTINUATION	$351,000
2021	2021	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90095	LOS ANGELES	USA	Vision Research	001	2	2/23/2021	NON-COMPETING CONTINUATION	$27,300
														Subtotal = $378,300

Issue Date FY: 2020 ( Subtotal = $390,000 )
2020	2020	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90095	LOS ANGELES	USA	Vision Research	000	1	1/27/2020	NEW	$390,000
														Subtotal = $390,000

Grand Total All Awards = $1,926,600

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Molecular, cellular, anatomical and neurobiological investigation of melanopsin-expressing corneal innervation, and its role in pain and photophobia

Award Number: R01EY030864

ORGANIZATION: NATIONAL EYE INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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