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Differential Effects of Corneal Hypoxia on Limbal Stem and Epithelial Cell Fates

Award Number: R01EY022364
ORGANIZATION: NATIONAL EYE INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2012
PERIOD OF PERFORMANCE END DATE: 08/31/2018

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Differential Effects of Corneal Hypoxia on Limbal Stem and Epithelial Cell Fates - DESCRIPTION (provided by applicant): The overall objective of this project is to define the molecular mechanisms of how human corneal Limbal Stem/Progenitor (LS/P) and Corneal Epithelial (CE) cells respond to hypoxic stresses in physiological and pathological conditions. Our preliminary data show in human CE cells that hypoxia (1% O2) activates Polo-like kinase 3 (Plk3) cascades that phosphorylate a group of important determinants for regulating cell fates, such as Hif-1, p53, c-Jun/AP-1 and H2AX. Thus, larger responses to hypoxic stress based on the magnitude of increases in Plk3 activities result in CE cell apoptosis. By contrast, human corneal LS/P cells are resistant to hypoxia-induced apoptosis because hypoxia suppresses Plk3 expression and fails to induce phosphorylation of Hif-1, p53, c-Jun/AP-1 and H2AX in these cells. We reveal that hypoxia stimulates significant changes in microRNA (miRNA) expression profiles. These miRNAs specifically target the 3'-untranslated region (3' UTR) of Plk3 mRNA to suppress hypoxia-induced Plk3 signaling in corneal LS/P cells, but not in CE cells. Our central hypothesis is that exposure of human corneas to hypoxic conditions activates two distinct processes in corneal LS/P and CE cells including: 1) activation of a Plk3-mediated signaling pathway that in turn increases p53 phosphorylation and activations of c-Jun/AP-1 and H2AX resulting in CE cell apoptosis; and 2) activation of specific expressions of miRNAs that suppress Plk3 expression to down-regulate downstream targets resulting in hypoxic tolerance and to trigger differentiation of corneal LS/P cells. To identify the molecular mechanisms, we propose three aims: 1) To define how hypoxia-induced Plk3 activation affects and interacts with AP-1, p53 and H2AX. Hypoxia-induced p53 and c-Jun phosphorylation are directly relevant to apoptosis. We will determine whether hypoxia-induced Plk3 can directly activate p53, AP-1 and H2AX, and how hypoxia-induced ATM/ATR/Chk1/2 activation leads to Plk3 activation in CE cells. 2) To investigate how Plk3 is down-regulated in hypoxia-induced corneal LS/P cells. Hypoxia suppresses Plk3 expression through a novel mechanism by inducing high levels of Plk3-specific miRNAs. We will determine the hypoxia-induced miRNA profiles in corneal LS/P cells in hypoxic conditions, which of the hypoxia-sensitive miRNAs suppress the Plk3 signaling pathway in the LS/P cells, and how these miRNAs interact with Plk3 mRNA to affect its stability. 3) To determine roles of hypoxia-induced Plk3 activation in corneal epithelial wound healing. Effects of hypoxia on corneal LS/P cell differentiation and CE cell apoptosis through regulating the Plk3 signaling pathways will be integrated in this aim. We investigate the effects of altered Plk3 activities on hypoxia-induced LS/P cell differentiation and CE cell apoptosis, and how hypoxia-induced delay of the wound healing process is affected by altering Plk3 activity in LS/P cells and corneas of Plk3-/- mice. By achieving the goal of combined studies, we will provide novel mechanisms to advance our understanding of hypoxia-induced effects on LS/P and CE cell functions in corneal epithelial self-renewal and wound healing.


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: 2019 ( Subtotal = -$1 )
2019	2016	LUNDQUIST INSTITUTE FOR BIOMEDICAL INNOVATION AT HARBOR-UCLA MEDICAL CENTER	1124 WEST CARSON ST.	TORRANCE	CA	90502	LOS ANGELES	USA	Vision Research	000	5	11/6/2018	EXTENSION WITH OR WITHOUT FUNDS	-$1
														Subtotal = -$1

Issue Date FY: 2017 ( Subtotal = $0 )
2017	2016	LOS ANGELES BIOMEDICAL RESEARCH INSTITUTE AT HARBOR-UCLA MEDICAL CENTER	1124 W CARSON ST BLDG N-14	TORRANCE	CA	90502	LOS ANGELES	USA	Vision Research	001	5	3/2/2017	EXTENSION WITH OR WITHOUT FUNDS	$84,338
2017	2015	LOS ANGELES BIOMEDICAL RESEARCH INSTITUTE AT HARBOR-UCLA MEDICAL CENTER	1124 W CARSON ST BLDG N-14	TORRANCE	CA	90502	LOS ANGELES	USA	Vision Research	000	4	3/2/2017	NON-COMPETING CONTINUATION	-$84,338
														Subtotal = $0

Issue Date FY: 2016 ( Subtotal = $328,300 )
2016	2016	LA BIOMEDICAL RESEARCH INSTITUTE AT HARBOR UCLA MED CTR	1124 WEST CARSON STREET	TORRANCE	CA	90502	LOS ANGELES	USA	Vision Research	000	5	8/10/2016	EXTENSION WITH OR WITHOUT FUNDS	$328,300
														Subtotal = $328,300

Issue Date FY: 2015 ( Subtotal = $321,734 )
2015	2015	LA BIOMEDICAL RESEARCH INSTITUTE AT HARBOR UCLA MED CTR	1124 WEST CARSON STREET	TORRANCE	CA	90502	LOS ANGELES	USA	Vision Research	000	4	8/5/2015	NON-COMPETING CONTINUATION	$321,734
														Subtotal = $321,734

Issue Date FY: 2014 ( Subtotal = $321,734 )
2014	2014	LA BIOMEDICAL RESEARCH INSTITUTE AT HARBOR UCLA MED CTR	1124 WEST CARSON STREET	TORRANCE	CA	90502	LOS ANGELES	USA	Vision Research	000	3	8/22/2014	NON-COMPETING CONTINUATION	$321,734
														Subtotal = $321,734

Issue Date FY: 2013 ( Subtotal = $311,885 )
2013	2013	LA BIOMEDICAL RESEARCH INSTITUTE AT HARBOR UCLA MED CTR	1124 WEST CARSON STREET	TORRANCE	CA	90502	LOS ANGELES	USA	Vision Research	000	2	8/16/2013	NON-COMPETING CONTINUATION	$311,885
														Subtotal = $311,885

Issue Date FY: 2012 ( Subtotal = $328,300 )
2012	2012	LA BIOMEDICAL RESEARCH INSTITUTE AT HARBOR UCLA MED CTR	1124 WEST CARSON STREET	TORRANCE	CA	90502	LOS ANGELES	USA	Vision Research	000	1	9/3/2012	NEW	$328,300
														Subtotal = $328,300

Grand Total All Awards = $1,611,952

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Differential Effects of Corneal Hypoxia on Limbal Stem and Epithelial Cell Fates

Award Number: R01EY022364

ORGANIZATION: NATIONAL EYE INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/01/2012

PERIOD OF PERFORMANCE END DATE: 08/31/2018

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