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The Role of MicroRNAs in Normal and Diseased Corneal Epithelial Homeostasis

Award Number: R01EY025377
ORGANIZATION: NATIONAL EYE INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/2015
PERIOD OF PERFORMANCE END DATE: 05/31/2027

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The Role of MicroRNAs in Normal and Diseased Corneal Epithelial Homeostasis - Corneal diseases and injuries leading to visual impairment have significant impact on the quality of life of patients and constitute a major problem for health care system. Corneal diseases are often manifested through limbal epithelial stem cell (LESC) dysfunction and loss, leading to corneal opacity, visual impairment, and blindness. LESC located in the limbal niche are the source of constant corneal epithelial renewal and are required to maintain corneal epithelial homeostasis by adapting properly to internal and external stimuli. However, persistent exposure to pathological stress disrupts the adaptive mechanisms of LESC, leading to serious corneal problems such as altered wound healing, limbal stem cell deficiency (LSCD) and diabetic keratopathy. Therefore, understanding the precise spatial and temporal regulatory pathways and how each LESC/limbal epithelial cells (LECs) responds to various stimuli at the single-cell level governing corneal epithelial regeneration could be key to elucidating the pathogenesis of various corneal diseases and ultimately developing new and effective treatment strategies. Previously, we have shown the important regulatory role of miR-146a in corneal epithelial homeostasis and wound healing via its different targeted pathways such as EGFR, Notch and NF-κB signaling. However, due to the heterogeneity of limbal basal cells and their proximity to limbal stromal cells, it remains to be determined how miRNAs (miRs) regulate maintenance, differentiation, and the active stage of limbal progenitor cells in various corneal cell populations in wounded and unwounded normal and diseased corneas. Recently several studies have shown the heterogeneity and complexity of limbal niche in relation to regeneration and wound healing and identified new putative LESC markers using newly emerged empowering scRNA-seq technology. We propose to investigate the regulatory role and contribution of each miR-146 main targets (EGFR, TRAF6, IRAK1, NUMB and NOTCH-2) in corneal epithelial regeneration in wounded and unwounded states in normal and diabetic corneas using scRNA-seq, proteomics, loss and gain of functional studies. We hypothesize that miR-146a contribute to the molecular regulation of cellular heterogeneity in the limbal niche steady state. We predict that differential miR-146a expression in limbus vs. central corneal epithelium impacts its regulation of limbal niche cells, LECs and limbal stromal cells, and mediates corneal regeneration and wound healing in normal and diseased states. Our Specific Aims are: Specific Aim 1: To identify and characterize downstream targets including EGFR, Notch and inflammatory mediators of miR-146a in distinct populations of heterogeneous limbal stem cells that contribute to homeostatic maintenance and regeneration in human normal unwounded and wounded cornea. Specific Aim 2: To reveal the differential and converged regulatory role of EGFR, inflammatory, and Notch signaling by miR-146a in corneal epithelial homeostasis and wound healing. Specific Aim 3: To investigate miR146a-based therapeutic approach by modulating its targets in human diabetic organ-cultured corneas.


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: 2026 ( Subtotal = $555,402 )
2026	2026	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	WEST HOLLYWOOD	CA	90048	LOS ANGELES	USA	Vision Research	000	9	6/5/2026	NON-COMPETING CONTINUATION	$555,402
														Subtotal = $555,402

Issue Date FY: 2025 ( Subtotal = $472,091 )
2025	2025	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	WEST HOLLYWOOD	CA	90048	LOS ANGELES	USA	Vision Research	000	8	9/19/2025	NON-COMPETING CONTINUATION	$472,091
														Subtotal = $472,091

Issue Date FY: 2024 ( Subtotal = $555,402 )
2024	2024	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	WEST HOLLYWOOD	CA	90048	LOS ANGELES	USA	Vision Research	000	7	5/22/2024	NON-COMPETING CONTINUATION	$555,402
														Subtotal = $555,402

Issue Date FY: 2023 ( Subtotal = $555,640 )
2023	2023	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	WEST HOLLYWOOD	CA	90048	LOS ANGELES	USA	Vision Research	001	6	7/31/2023	COMPETING CONTINUATION	$555,402
2023	2019	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	WEST HOLLYWOOD	CA	90048	LOS ANGELES	USA	Vision Research	000	5	11/23/2022	NON-COMPETING CONTINUATION	$238
														Subtotal = $555,640

Issue Date FY: 2022 ( Subtotal = -$12,297 )
2022	2019	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	WEST HOLLYWOOD	CA	90048	LOS ANGELES	USA	Vision Research	000	5	2/15/2022	NON-COMPETING CONTINUATION	-$12,297
														Subtotal = -$12,297

Issue Date FY: 2019 ( Subtotal = $437,500 )
2019	2019	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	LOS ANGELES	CA	90048	LOS ANGELES	USA	Vision Research	000	5	7/17/2019	NON-COMPETING CONTINUATION	$437,500
														Subtotal = $437,500

Issue Date FY: 2018 ( Subtotal = $437,500 )
2018	2018	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	LOS ANGELES	CA	90048	LOS ANGELES	USA	Vision Research	000	4	7/30/2018	NON-COMPETING CONTINUATION	$437,500
														Subtotal = $437,500

Issue Date FY: 2017 ( Subtotal = $437,500 )
2017	2017	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	LOS ANGELES	CA	90048	LOS ANGELES	USA	Vision Research	000	3	7/24/2017	NON-COMPETING CONTINUATION	$437,500
														Subtotal = $437,500

Issue Date FY: 2016 ( Subtotal = $437,500 )
2016	2016	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD, METRO 203	LOS ANGELES	CA	90048	LOS ANGELES	USA	Vision Research	000	2	7/4/2016	NON-COMPETING CONTINUATION	$437,500
														Subtotal = $437,500

Issue Date FY: 2015 ( Subtotal = $418,750 )
2015	2015	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD, METRO 203	LOS ANGELES	CA	90048	LOS ANGELES	USA	Vision Research	000	1	7/17/2015	NEW	$418,750
														Subtotal = $418,750

Grand Total All Awards = $4,294,987

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The Role of MicroRNAs in Normal and Diseased Corneal Epithelial Homeostasis

Award Number: R01EY025377

ORGANIZATION: NATIONAL EYE INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/01/2015

PERIOD OF PERFORMANCE END DATE: 05/31/2027

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