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Toolkit for High-Resolution Structure and Dynamics of Functional Lipids

Award Number: R01GM123455
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/13/2016
PERIOD OF PERFORMANCE END DATE: 07/31/2023

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Toolkit for High-Resolution Structure and Dynamics of Functional Lipids - Project Summary Membrane proteins are abundant in eukaryotic cells and play important roles in a great many biological processes ranging from cell adhesion and recognition to energy production to signaling cascades. Furthermore, membrane proteins make up about 60% of the targets for currently approved drugs, which underscores their relevance to human disease. Although very high resolution structures of a number of membrane proteins have now been solved, we lack methods that will also allow us to resolve the structures of the membrane lipids that interact with membrane-embedded proteins, peripheral membrane proteins and other ligands. This is in spite of the fact that specific membrane lipids play key regulatory roles in biology. We term these “functional lipids” because, in addition to their well-known structural roles in membranes, it is becoming increasingly clear that lipids are effector molecules that modulate and/or directly carry out essential biological functions. An atomic-scale understanding of the interactions carried out by functional lipids is an important unmet goal with direct relevance to human health and disease. Thus, although excellent methods now exist for solving the structures of proteins—including membrane proteins—at very high resolution, the field lacks tools necessary to solve the structures of the lipid part of membranes at high resolution. This ambitious project aims to develop an innovative “toolkit” of high-resolution methods for the scientific community to use in solving the structures of lipids that regulate the biological functions of membranes. Our approach requires synergistic and coordinated efforts throughout: (1) cost-effective, site-specific isotopic labeling of a variety of phospholipids and sterols; (2) assembling labeled lipids into nanoscale lipid bilayer systems together with their biologically relevant ligands; (3) nuclear magnetic resonance (NMR) approaches, principally high-field magic-angle spinning solid-state NMR (SSNMR), to obtain detailed structural information about the lipids interacting with ligands; (4) cutting-edge computational methods employing molecular dynamics (MD) simulations of lipids interacting with ligands in bilayers or bilayer mimetics; and (5) new methods for solving lipid structures by marrying computational NMR and MD approaches to address the unique challenges inherent in interpreting and understanding spectral data obtained from planar bilayers that contain repeating copies of labeled lipids interacting with neighboring lipids in addition to their specific ligands. As our studies progress, we propose to apply this toolkit to exemplary problems in biology, including blood coagulation, antimicrobial peptide action and sterol recognition.


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 = $0 )
2026	2020	UNIVERSITY OF ILLINOIS	506 S WRIGHT ST	URBANA	IL	61801	CHAMPAIGN	USA	Biomedical Research and Research Training	000	5	10/10/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2020	UNIVERSITY OF ILLINOIS	506 S WRIGHT ST	URBANA	IL	61801	CHAMPAIGN	USA	Biomedical Research and Research Training	000	5	4/16/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $0 )
2022	2020	UNIVERSITY OF ILLINOIS	506 S WRIGHT ST	URBANA	IL	61801	CHAMPAIGN	USA	Biomedical Research and Research Training	000	5	7/20/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2020 ( Subtotal = $955,103 )
2020	2020	UNIVERSITY OF ILLINOIS	364 HENRY ADMINISTRATION BLDG	URBANA	IL	61801	CHAMPAIGN	USA	Biomedical Research and Research Training	000	5	7/30/2020	NON-COMPETING CONTINUATION	$955,103
														Subtotal = $955,103

Issue Date FY: 2019 ( Subtotal = $955,103 )
2019	2019	UNIVERSITY OF ILLINOIS	364 HENRY ADMINISTRATION BLDG	URBANA	IL	61801	CHAMPAIGN	USA	Biomedical Research and Research Training	000	4	7/30/2019	NON-COMPETING CONTINUATION	$955,103
														Subtotal = $955,103

Issue Date FY: 2018 ( Subtotal = $955,103 )
2018	2018	UNIVERSITY OF ILLINOIS	506 S WRIGHT ST STE 364	URBANA	IL	61801	CHAMPAIGN	USA	Biomedical Research and Research Training	000	3	7/30/2018	NON-COMPETING CONTINUATION	$955,103
														Subtotal = $955,103

Issue Date FY: 2017 ( Subtotal = $955,103 )
2017	2017	UNIVERSITY OF ILLINOIS	506 S WRIGHT ST STE 364	URBANA	IL	61801	CHAMPAIGN	USA	Biomedical Research and Research Training	000	2	7/24/2017	NON-COMPETING CONTINUATION	$955,103
														Subtotal = $955,103

Issue Date FY: 2016 ( Subtotal = $1,177,047 )
2016	2016	UNIVERSITY OF ILLINOIS BOARD OF TRUSTEES	109 COBLE HALL, 801 S WRIGHT S	CHAMPAIGN	IL	61820	CHAMPAIGN	USA	Biomedical Research and Research Training	000	1	9/13/2016	NEW	$1,177,047
														Subtotal = $1,177,047

Grand Total All Awards = $4,997,459

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Toolkit for High-Resolution Structure and Dynamics of Functional Lipids

Award Number: R01GM123455

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/13/2016

PERIOD OF PERFORMANCE END DATE: 07/31/2023

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