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Structural analysis of protein-protein and protein-lipid interactions of lens membrane proteins.

Award Number: F31EY032348
ORGANIZATION: NATIONAL EYE INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 12/01/2021
PERIOD OF PERFORMANCE END DATE: 12/31/2023

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Structural analysis of protein-protein and protein-lipid interactions of lens membrane proteins. - Summary/abstract: Cataract is the leading cause of blindness worldwide, costing the US Healthcare system billions of dollars annually for surgical treatment. Lens opacification has been linked to dysfunction in major membrane proteins, Aquaporin-0 (AQP0) and Lim2. The overall goal of my project is to develop a comprehensive understanding of the structure and function of protein-protein and protein-lipid interactions of these membrane proteins. In the absence of a blood supply, the microcirculation system transports nutrients and removes wastes to inner fiber cells and is essential for maintaining lens transparency over decades of life; however, how this microcirculation system is established and maintained as a function of age is not well understood. Using advanced mass spectrometry techniques such as hydrogen-deuterium exchange-MS, native-MS and chemical crosslinking studies, I intend to elucidate how specific protein and lipid interactions impact the structure and function of AQP0 and Lim2; membrane proteins that are fundamental to the microcirculation system of the lens. The most abundant lens membrane protein, AQP0, plays important roles in lens fiber cell adhesion and water permeability with water permeability regulated by interaction with the calcium-binding protein, calmodulin. Data from my lab and others demonstrated that calmodulin interacts with the C-terminal tail of AQP0; however, molecular dynamic (MD) simulations suggest a non-canonical interaction with a cytosolic loop of AQP0. This MD prediction has not been experimentally validated. In addition to AQP0- protein interactions (Aim 1), I hypothesize that AQP0-lipid interactions (Aim 2) regulate AQP0 permeability and adhesion properties that underlie lens transparency; however, there are limited reports on AQP0 interactions with native lipids. Given the vital role of AQP0 in maintaining lens transparency and its connection to cataract, understanding regulatory interactions with proteins such as calmodulin and native lipids will clarify its role in the microcirculation system. The second most abundant membrane protein in the lens is Lim2 and, like AQP0, its mutation has been associated with cataractogenesis in mice; however, little is known about Lim2-protein interactions (Aim 1). Binding partners to Lim2 have been reported, i.e. calmodulin and galectin-3, but how these interactions modulate Lim2 structure and function are not clear. Additionally, native lens lipids have been reported to impact Lim2 subunit assembly, but the details underlying this phenomenon have not been explored. As a result of the scarcity of experimental research on Lim2-native lipid interactions (Aim 2), I will use native MS to identify specific lipid interactions and determine how they affect Lim2 structure. My findings will aid researchers develop therapeutic targets and/or practices that can prevent, reverse or delay cataract formation.


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: 2025 ( Subtotal = -$690 )
2025	2024	VANDERBILT UNIVERSITY	110 21ST AVE S	NASHVILLE	TN	37203	DAVIDSON	USA	Vision Research	000	3	10/23/2024	NON-COMPETING CONTINUATION	-$690
														Subtotal = -$690

Issue Date FY: 2024 ( Subtotal = $7,727 )
2024	2024	VANDERBILT UNIVERSITY	110 21ST AVE S	NASHVILLE	TN	37203	DAVIDSON	USA	Vision Research	000	3	11/17/2023	NON-COMPETING CONTINUATION	$7,037
2024	2024	VANDERBILT UNIVERSITY	110 21ST AVE S	NASHVILLE	TN	37203	DAVIDSON	USA	Vision Research	001	3	6/7/2024	NON-COMPETING CONTINUATION	$690
														Subtotal = $7,727

Issue Date FY: 2023 ( Subtotal = $34,978 )
2023	2023	VANDERBILT UNIVERSITY	110 21ST AVE S	NASHVILLE	TN	37203	DAVIDSON	USA	Vision Research	000	2	12/1/2022	NON-COMPETING CONTINUATION	$34,036
2023	2023	VANDERBILT UNIVERSITY	110 21ST AVE S	NASHVILLE	TN	37203	DAVIDSON	USA	Vision Research	001	2	3/8/2023	NON-COMPETING CONTINUATION	$942
														Subtotal = $34,978

Issue Date FY: 2022 ( Subtotal = $2,500 )
2022	2022	VANDERBILT UNIVERSITY, THE	110 21ST AVENUE S STE 800	NASHVILLE	TN	37203	DAVIDSON	USA	Vision Research	001	1	2/3/2022	SUPPLEMENT FOR EXPANSION	$2,500
2022	2021	VANDERBILT UNIVERSITY, THE	110 21ST AVENUE S STE 800	NASHVILLE	TN	37203	DAVIDSON	USA	Vision Research	000	1	12/16/2021	NEW	$0
														Subtotal = $2,500

Issue Date FY: 2021 ( Subtotal = $30,811 )
2021	2021	VANDERBILT UNIVERSITY, THE	110 21ST AVENUE S STE 800	NASHVILLE	TN	37203	DAVIDSON	USA	Vision Research	000	1	9/17/2021	NEW	$30,811
														Subtotal = $30,811

Grand Total All Awards = $75,326

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Structural analysis of protein-protein and protein-lipid interactions of lens membrane proteins.

Award Number: F31EY032348

ORGANIZATION: NATIONAL EYE INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 12/01/2021

PERIOD OF PERFORMANCE END DATE: 12/31/2023

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