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SLC4A11 Mitochondrial Uncoupling and ROS Production in Corneal Endothelium

Award Number: R01EY031321
ORGANIZATION: NATIONAL EYE INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/01/2020
PERIOD OF PERFORMANCE END DATE: 04/30/2024

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SLC4A11 Mitochondrial Uncoupling and ROS Production in Corneal Endothelium - “SLC4A11 Mitochondrial Uncoupling and ROS Production in Corneal Endothelium” ABSTRACT Defects in the gene SLC4A11 cause Congenital Hereditary Endothelial Dystrophy and some forms of Fuchs Dystrophy. The goal of this study is to understand the role of this membrane transporter in normal corneal endothelial metabolism and how SLC4A11 deficiency leads to Corneal Dystrophy. The corneal endothelial “pump” maintains corneal hydration and transparency. When the “pump” fails due to trauma, inflammation, ageing, or dystrophy, corneal edema ensues, transparency is lost, and vision is significantly degraded. The usual therapy is transplantation, which is not without significant compromises and complications. A hallmark of Corneal Endothelial Dystrophies is mitochondrial dysfunction. Our laboratory has shown that SLC4A11 is an NH3 dependent electrogenic H+ transporter. We have found that glutamine is actively metabolized by the endothelium producing NH3 and enhancing ATP formation. Slc4a11 knock out shows significant corneal edema, lactate accumulation, altered mitochondrial physiology, and ROS. These data have led to the overarching hypothesis that corneal endothelium actively metabolize glutamine and that the absence of SLC4A11 alters glutamine metabolism, leading to mitochondrial dysfunction, ROS, and eventual apoptosis. Preliminary data indicate that SLC4A11 is both a plasma membrane and a mitochondrial membrane protein, leading to the novel hypothesis that SLC4A11 is a mitochondrial uncoupler. Using multiple in vitro & in vivo complementary approaches these hypotheses will be tested in three aims. Aim 1 will determine how glutamine metabolism is facilitated in Corneal Endothelial mitochondria. The hypothesis is that Slc4a11 is an NH3 sensitive mitochondrial uncoupler that works in conjunction with Uncoupling Protein-2 and the potential mitochondrial buffer taurine to facilitate Glutamine catabolism. Aim 2 will examine the source of ROS and ROS as a stimulus to Apoptosis in Slc4a11 KO. Our hypothesis is that apoptosis is accelerated by ROS, which is generated by the interaction of NH3 with an energized electron transport chain and reduced by SLC4A11 uncoupling. Aim 3 will identify the cause of corneal edema in Slc4a11 KO Mice. We will test the hypothesis that loss of Slc4a11 secondarily induces downregulation of key proteins that facilitate lactate transport. Completion of this study will establish the role of SLC4A11 and glutamine in endothelial metabolism; provide new insight for mechanisms that facilitate glutamine metabolism yet alleviate NH3 induced ROS production that will be transferable to a wide array of glutamine metabolizing tissues; and provide insight for development of therapies for endothelial dystrophies.


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: 2023 ( Subtotal = $424,790 )
2023	2023	TRUSTEES OF INDIANA UNIVERSITY	107 S INDIANA AVE	BLOOMINGTON	IN	47405	MONROE	USA	Vision Research	000	4	7/14/2023	NON-COMPETING CONTINUATION	$424,790
														Subtotal = $424,790

Issue Date FY: 2022 ( Subtotal = $412,045 )
2022	2022	TRUSTEES OF INDIANA UNIVERSITY	107 S INDIANA AVE	BLOOMINGTON	IN	47405	MONROE	USA	Vision Research	000	3	4/29/2022	NON-COMPETING CONTINUATION	$412,045
														Subtotal = $412,045

Issue Date FY: 2021 ( Subtotal = $412,046 )
2021	2021	TRUSTEES OF INDIANA UNIVERSITY	107 S INDIANA AVENUE	BLOOMINGTON	IN	47405	MONROE	USA	Vision Research	000	2	4/15/2021	NON-COMPETING CONTINUATION	$412,046
														Subtotal = $412,046

Issue Date FY: 2020 ( Subtotal = $424,790 )
2020	2020	TRUSTEES OF INDIANA UNIVERSITY	107 S INDIANA AVENUE	BLOOMINGTON	IN	47405	MONROE	USA	Vision Research	000	1	4/8/2020	NEW	$424,790
														Subtotal = $424,790

Grand Total All Awards = $1,673,671

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SLC4A11 Mitochondrial Uncoupling and ROS Production in Corneal Endothelium

Award Number: R01EY031321

ORGANIZATION: NATIONAL EYE INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 05/01/2020

PERIOD OF PERFORMANCE END DATE: 04/30/2024

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