Wednesday, January 15, 2025 1/15/2025

Pathogenic Alterations of the 3D Epigenetic Landscape in Dystrophin-Deficient Skeletal Muscles and Reversal by Dystrophin Re-Expression

Award Number: R01AR056712
ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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PROJECT SUMMARY Lack of dystrophin (dys) and disruption of the dys-associated protein complex (DAPC) at the membrane of skeletal myofibers are widely recognized as the main cause of sarcolemma instability, leading to skeletal muscle loss in patients affected by Duchenne Muscular Dystrophy (DMD). In addition to its structural function, dys has been implicated in the regulation of additional downstream cellular events, including control of the genome integrity and gene expression. Indeed, dys-deficient muscles exhibit altered profiles of histone modifications, gene expression and non-coding RNA, as well as features of genomic instability and nuclear abnormalities. Chromosome conformation capture (3C)-based studies have revealed that the genome is folded into high-order chromatin interactions. Understanding the relationship between dys deficiency, dysregulated gene expression and altered genome topology is of special interest for the complete understanding of DMD pathogenesis and for the evaluation of the effective benefits of therapeutic approaches aimed at replacing dys expression in DMD boys. This proposal addresses this question by exploiting state-of-the-art genome-wide approaches (i.e. promoter capture-HiC, ChIP-seq, ATAC-seq and RNAseq) to detect perturbations of the epigenetic landscape and transcriptome in DMD muscles, using two complementary experimental models – patient iPSC-based in dish model of human DMD vivo and the mdx mouse model in vivo, by the following Aims: Aim 1. To identify alterations in high-order chromatin interactions that regulate gene expression in DMD muscles We will identify alterations of chromatin interactions between functional and structural genomic elements, leading to pathogenic gene expression in human (hiPSC-derived skeletal muscles) and mouse (mdx mice) models of DMD. Aim 2. Effect of µ-dys restoration on reversal of alterations in high- order chromatin interactions that regulate gene expression in DMD muscles We will evaluate whether restoration of dys expression by µ-dys reverses (partly or completely) the epigenetic and transcriptional alterations of DMD muscles identified in Aim 1. Aim 3. Bioinformatic identification and analysis of epigenetic and transcriptional alterations in DMD muscles We will perform an integrated bioinformatic analysis of pcHi-C, RNA-seq, ATAC-seq and ChIP-seq data to identify DMD-associated pathogenic chromatin interactions (DMD PCI) in DMD MuSCs and myofibers, and their susceptibility to µ-dys expression. Aim 4. Contraction-induced alterations in high-order chromatin interactions at pathogenic loci in DMD muscles and reversibility by dys restoration We will determine the effect of muscle contraction on PCI and gene expression at loci of pathogenic genes, within the context of dys deficiency and upon µ-dys recovery. Understanding whether dys deficiency causes epigenetic perturbations responsible for pathogenic transcriptional output of DMD muscles, and whether they could be reversed by µ-dys expression, will invariably extend our knowledge on DMD pathogenesis and on the therapeutic efficacy of µ-dys based gene therapies.


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: 2024 ( Subtotal = $636,717 )
2024	2024	SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE	10901 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	13	6/3/2024	NON-COMPETING CONTINUATION	$636,717
														Subtotal = $636,717

Issue Date FY: 2023 ( Subtotal = $652,976 )
2023	2023	SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE	10901 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	12	5/25/2023	NON-COMPETING CONTINUATION	$652,976
														Subtotal = $652,976

Issue Date FY: 2022 ( Subtotal = $676,726 )
2022	2022	SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE	10901 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	11	8/3/2022	COMPETING CONTINUATION	$0
2022	2022	SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE	10901 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	002	11	9/22/2022	COMPETING CONTINUATION	$0
2022	2022	SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE	10901 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	11	5/31/2022	COMPETING CONTINUATION	$676,726
														Subtotal = $676,726

Issue Date FY: 2020 ( Subtotal = $0 )
2020	2018	SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE	10901 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	10	1/4/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2018 ( Subtotal = $429,000 )
2018	2018	SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE	10901 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	10	8/3/2018	NON-COMPETING CONTINUATION	$429,000
														Subtotal = $429,000

Issue Date FY: 2017 ( Subtotal = $429,000 )
2017	2017	SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE	10901 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	9	7/28/2017	NON-COMPETING CONTINUATION	$429,000
														Subtotal = $429,000

Issue Date FY: 2016 ( Subtotal = $429,000 )
2016	2016	SANFORD-BURNHAM MEDICAL RESEARCH INSTITUTE	10901 NORTH TORREY PINES ROAD	LA JOLLA	CA	92037	SAN DIEGO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	8	8/10/2016	NON-COMPETING CONTINUATION	$429,000
														Subtotal = $429,000

Issue Date FY: 2015 ( Subtotal = $429,000 )
2015	2015	SANFORD-BURNHAM MEDICAL RESEARCH INSTITUTE	10901 NORTH TORREY PINES ROAD	LA JOLLA	CA	92037	SAN DIEGO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	7	9/2/2015	NON-COMPETING CONTINUATION	$429,000
														Subtotal = $429,000

Issue Date FY: 2014 ( Subtotal = $429,000 )
2014	2014	SANFORD-BURNHAM MEDICAL RESEARCH INSTITUTE	10901 NORTH TORREY PINES ROAD	LA JOLLA	CA	92037	SAN DIEGO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	6	7/24/2014	COMPETING CONTINUATION	$429,000
														Subtotal = $429,000

Issue Date FY: 2013 ( Subtotal = $396,139 )
2013	2013	SANFORD-BURNHAM MEDICAL RESEARCH INSTITUTE	10901 NORTH TORREY PINES ROAD	LA JOLLA	CA	92037	SAN DIEGO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	5	8/6/2013	NON-COMPETING CONTINUATION	$396,139
														Subtotal = $396,139

Issue Date FY: 2012 ( Subtotal = $416,988 )
2012	2012	SANFORD-BURNHAM MEDICAL RESEARCH INSTITUTE	10901 NORTH TORREY PINES ROAD	LA JOLLA	CA	92037	SAN DIEGO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	4	7/27/2012	NON-COMPETING CONTINUATION	$416,988
														Subtotal = $416,988

Issue Date FY: 2011 ( Subtotal = $408,434 )
2011	2011	SANFORD-BURNHAM MEDICAL RESEARCH INSTITUTE	10901 NORTH TORREY PINES ROAD	LA JOLLA	CA	92037	SAN DIEGO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	3	7/19/2011	NON-COMPETING CONTINUATION	$408,434
														Subtotal = $408,434

Issue Date FY: 2010 ( Subtotal = $425,453 )
2010	2010	BURNHAM INSTITUTE FOR MEDICAL RESEARCH	10901 NORTH TORREY PINES ROAD	LA JOLLA	CA	92037	SAN DIEGO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	002	2	7/21/2010	NON-COMPETING CONTINUATION	$425,453
2010	2009	BURNHAM INSTITUTE FOR MEDICAL RESEARCH	10901 NORTH TORREY PINES ROAD	LA JOLLA	CA	92037	SAN DIEGO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	3/29/2010	NEW	$0
2010	2009	BURNHAM INSTITUTE FOR MEDICAL RESEARCH	10901 NORTH TORREY PINES ROAD	LA JOLLA	CA	92037	SAN DIEGO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	1	3/29/2010	NEW	$0
														Subtotal = $425,453

Issue Date FY: 2009 ( Subtotal = $429,750 )
2009	2009	BURNHAM INSTITUTE FOR MEDICAL RESEARCH	10901 NORTH TORREY PINES ROAD	LA JOLLA	CA	92037	SAN DIEGO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	8/3/2009	NEW	$429,750
2009	2009	BURNHAM INSTITUTE FOR MEDICAL RESEARCH	10901 NORTH TORREY PINES ROAD	LA JOLLA	CA	92037	SAN DIEGO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	1	8/5/2009	NEW	$0
														Subtotal = $429,750

Grand Total All Awards = $6,188,183

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Pathogenic Alterations of the 3D Epigenetic Landscape in Dystrophin-Deficient Skeletal Muscles and Reversal by Dystrophin Re-Expression

Award Number: R01AR056712

ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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