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Role of ABCG1, ABCG5 and ABCG8 in Sterol Metabolism

Award Number: R01HL072304
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/01/2003
PERIOD OF PERFORMANCE END DATE: 11/30/2025

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Role of ABCG1, ABCG5 and ABCG8 in Sterol Metabolism - Cholesterol is continually acquired by de novo synthesis or from the diet and must be metabolized or excreted in order to maintain cholesterol homeostasis. In vertebrate animals, cholesterol can be actively excreted via members of the ATP-binding cassette G (ABCG) subfamily. In the liver, cholesterol is secreted into bile by a heterodimer of ABCG5 and ABCG8 (G5G8). In the intestine, G5G8 limits the absorption of dietary sterols. Inactivation of G5 or G8 causes sitosterolemia, a recessive disorder associated with sterol accumulation and premature atherosclerosis. Another ABCG family member, ABCG1 (G1) also transports cholesterol. Unlike G5/G8, G1 functions as a homodimer and promotes the export of phospholipids and sphingomyelin, as well as cholesterol, from cells. G1 participates in the transport of cholesterol from peripheral tissues, where is it synthesized, through the circulation to the liver for excretion into bile. The overall goal of our research program is to determine how G5G8 and G1 promote the translocation of neutral sterols across biological membranes. In the last funding period, we used X-ray crystallography and cryo-electron microscopy (EM) to obtain high-resolution structures of nucleotide-free G5G8 with its cholesterol substrate at 2.7-3.0 Å resolution and both nucleotide-free and ATP-bound G1 at 3.1-3.7Å resolution. These results provided the first insights into the basic structure-function mechanisms of ABCG transporters and formed the basis of this grant application, which is designed to address 3 fundamental questions: 1) How do the conformations of G1 and G5G8 change during the transport cycle, and how do these changes relate to sterol translocation? 2) How do G1 and G5G8 recognize highly insoluble neutral sterols that are embedded in lipid bilayers and what accounts for the substrate specificity of the two transporters? And 3) How is substrate binding related to ATPase activity, and what is the structural basis for substrate-stimulated ATPase activity? Each of these questions is organized as a Specific Aim. The studies proposed take advantage of new developments in cryo-EM, our expertise in functional reconstitution of polytopic membrane proteins in vivo and in vitro, and our discovery of missense mutations in G5 and G8 with very specific effects on G5G8 and G1 function (e.g. large changes in substrate specificity or ATPase activity) that provide unique mechanistic insights. We have marshalled the reagents and expertise required to ensure successful completion of the studies proposed. Elucidation of the transport mechanisms of G1 and G5G8 will reveal how cells and organisms efflux lipids and maintain sterol balance, thus preventing two common disorders: coronary artery disease (CAD) and gallstones.


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 = $620,550 )
2025	2025	THE UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Cardiovascular Diseases Research	000	23	11/20/2024	NON-COMPETING CONTINUATION	$620,550
														Subtotal = $620,550

Issue Date FY: 2024 ( Subtotal = $675,710 )
2024	2024	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Cardiovascular Diseases Research	000	22	11/15/2023	NON-COMPETING CONTINUATION	$620,550
2024	2024	THE UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Cardiovascular Diseases Research	001	22	7/13/2024	NON-COMPETING CONTINUATION	$55,160
														Subtotal = $675,710

Issue Date FY: 2023 ( Subtotal = $689,500 )
2023	2023	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Cardiovascular Diseases Research	000	21	11/25/2022	NON-COMPETING CONTINUATION	$620,550
2023	2023	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Cardiovascular Diseases Research	001	21	2/11/2023	NON-COMPETING CONTINUATION	$68,950
														Subtotal = $689,500

Issue Date FY: 2022 ( Subtotal = $689,500 )
2022	2022	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Cardiovascular Diseases Research	001	20	11/24/2021	COMPETING CONTINUATION	$689,500
2022	2022	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Cardiovascular Diseases Research	003	20	4/22/2022	COMPETING CONTINUATION	$206,143
2022	2021	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Cardiovascular Diseases Research	002	19	4/22/2022	NON-COMPETING CONTINUATION	-$206,143
2022	2021	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Cardiovascular Diseases Research	000	19	11/23/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $689,500

Issue Date FY: 2021 ( Subtotal = $596,938 )
2021	2021	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Cardiovascular Diseases Research	000	19	12/4/2020	NON-COMPETING CONTINUATION	$537,245
2021	2021	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Cardiovascular Diseases Research	001	19	5/18/2021	NON-COMPETING CONTINUATION	$59,693
														Subtotal = $596,938

Issue Date FY: 2020 ( Subtotal = $583,861 )
2020	2020	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Cardiovascular Diseases Research	001	18	1/23/2020	NON-COMPETING CONTINUATION	$29,193
2020	2020	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Cardiovascular Diseases Research	000	18	11/29/2019	NON-COMPETING CONTINUATION	$554,668
														Subtotal = $583,861

Issue Date FY: 2019 ( Subtotal = $596,938 )
2019	2019	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Cardiovascular Diseases Research	000	17	12/11/2018	NON-COMPETING CONTINUATION	$596,938
														Subtotal = $596,938

Issue Date FY: 2018 ( Subtotal = $677,924 )
2018	2018	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Cardiovascular Diseases Research	000	16	12/26/2017	COMPETING CONTINUATION	$581,922
2018	2018	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Cardiovascular Diseases Research	001	16	4/27/2018	COMPETING CONTINUATION	$96,002
														Subtotal = $677,924

Issue Date FY: 2009 ( Subtotal = $0 )
2009	2007	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CTR DALLAS	5323 HARRY HINES BOULEVARD	DALLAS	TX	75235	DALLAS	USA	Cardiovascular Diseases Research	000	5	7/23/2009	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2008 ( Subtotal = $409,376 )
2008	2008	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CTR DALLAS	5323 HARRY HINES BOULEVARD	DALLAS	TX	75235	DALLAS	USA	Cardiovascular Diseases Research	000	6	2/1/2008	COMPETING CONTINUATION	$409,376
														Subtotal = $409,376

Issue Date FY: 2007 ( Subtotal = $369,790 )
2007	2007	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CTR DALLAS	5323 HARRY HINES BOULEVARD	DALLAS	TX	75235	DALLAS	USA	Cardiovascular Diseases Research	000	5	1/25/2007	NON-COMPETING CONTINUATION	$369,790
														Subtotal = $369,790

Issue Date FY: 2006 ( Subtotal = $380,835 )
2006	2006	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CTR DALLAS	5323 HARRY HINES BOULEVARD	DALLAS	TX	75235	DALLAS	USA	Cardiovascular Diseases Research	000	4	2/13/2006	NON-COMPETING CONTINUATION	$380,835
														Subtotal = $380,835

Issue Date FY: 2005 ( Subtotal = $390,000 )
2005	2005	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CTR DALLAS	5323 HARRY HINES BOULEVARD	DALLAS	TX	75235	DALLAS	USA	Cardiovascular Diseases Research	000	3	2/3/2005	NON-COMPETING CONTINUATION	$390,000
														Subtotal = $390,000

Issue Date FY: 2004 ( Subtotal = $390,000 )
2004	2004	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CTR DALLAS	5323 HARRY HINES BOULEVARD	DALLAS	TX	75235	DALLAS	USA	Cardiovascular Diseases Research	000	2	1/28/2004	NON-COMPETING CONTINUATION	$390,000
														Subtotal = $390,000

Issue Date FY: 2003 ( Subtotal = $390,000 )
2003	2003	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CTR DALLAS	5323 HARRY HINES BOULEVARD	DALLAS	TX	75235	DALLAS	USA	Cardiovascular Diseases Research	000	1		NEW	$390,000
														Subtotal = $390,000

Grand Total All Awards = $7,460,922

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Role of ABCG1, ABCG5 and ABCG8 in Sterol Metabolism

Award Number: R01HL072304

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 02/01/2003

PERIOD OF PERFORMANCE END DATE: 11/30/2025

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