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Molecular Regulation of LDL Receptor Expression

Award Number: R01HL167733
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/01/2024
PERIOD OF PERFORMANCE END DATE: 11/30/2028

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Molecular Regulation of LDL Receptor Expression - PROJECT SUMMARY The expression level of the LDL receptor (LDLR) in the liver is a major determinant of an individual’s lifetime risk of atherosclerotic cardiovascular disease (ASCVD). Although SREBP signaling plays an important role in LDLR gene regulation, it is highly likely that other transcription factors bind to noncoding cis-regulatory elements to further modulate LDLR expression. In particular, several common genetic variants within a ~20 kb interval near the LDLR transcription start site are each strongly associated with LDL cholesterol and ASCVD risk in human genome-wide association studies. Since many of these variants are co-inherited, however, it is unclear which are causal for an alteration in LDLR gene expression. In preliminary studies, we have performed a high-throughput CRISPR screen that revealed a strong functional influence on LDLR expression for a ~0.6 kb region within the first intron of LDLR, with minimal effect observed for the remainder of the ~20 kb GWAS- associated interval. This region furthermore exhibits biochemical features of enhancer activity, an enrichment in transcription factor binding motifs, and a high degree of evolutionary conservation among vertebrates. In this proposal, we seek to build upon this discovery to test our central hypothesis that an enhancer in the first intron of LDLR modulates its expression and the risk of ASCVD. In Aim 1, we will fine map the activity of the LDLR enhancer and identify the transcription factors that govern its effect. In Aim 2, we will generate mice with deletion of the first intronic Ldlr enhancer or its replacement with the homologous human sequence to establish its physiologic significance to lipoprotein metabolism in vivo. In Aim 3, we will engineer a synthetic version of the LDLR enhancer with optimized activity as a potential target for therapeutic genome editing. Together this work will clarify the fundamental biology of LDLR gene regulation and lay the groundwork for the long-term development of a novel genome editing strategy to prevent and treat ASCVD.


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 = $588,278 )
2026	2026	REGENTS OF THE UNIVERSITY OF MICHIGAN	1109 GEDDES AVE STE 3300	ANN ARBOR	MI	48109	WASHTENAW	USA	Cardiovascular Diseases Research	000	3	2/13/2026	NON-COMPETING CONTINUATION	$588,278
														Subtotal = $588,278

Issue Date FY: 2025 ( Subtotal = $619,239 )
2025	2025	REGENTS OF THE UNIVERSITY OF MICHIGAN	1109 GEDDES AVE STE 3300	ANN ARBOR	MI	48109	WASHTENAW	USA	Cardiovascular Diseases Research	001	2	8/19/2025	NON-COMPETING CONTINUATION	$61,924
2025	2025	REGENTS OF THE UNIVERSITY OF MICHIGAN	1109 GEDDES AVE, SUITE 3300	ANN ARBOR	MI	48109	WASHTENAW	USA	Cardiovascular Diseases Research	000	2	11/20/2024	NON-COMPETING CONTINUATION	$557,315
														Subtotal = $619,239

Issue Date FY: 2024 ( Subtotal = $625,479 )
2024	2024	REGENTS OF THE UNIVERSITY OF MICHIGAN	1109 GEDDES AVE, SUITE 3300	ANN ARBOR	MI	48109	WASHTENAW	USA	Cardiovascular Diseases Research	001	1	5/31/2024	NEW	$62,548
2024	2024	REGENTS OF THE UNIVERSITY OF MICHIGAN	1109 GEDDES AVE, SUITE 3300	ANN ARBOR	MI	48109	WASHTENAW	USA	Cardiovascular Diseases Research	000	1	12/14/2023	NEW	$562,931
														Subtotal = $625,479

Grand Total All Awards = $1,832,996

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Molecular Regulation of LDL Receptor Expression

Award Number: R01HL167733

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 01/01/2024

PERIOD OF PERFORMANCE END DATE: 11/30/2028

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