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The Role of Lipin1 in Myofiber Stability and Integrity

Award Number: R01AR077574
ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/22/2021
PERIOD OF PERFORMANCE END DATE: 05/31/2027

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The Role of Lipin1 in Myofiber Stability and Integrity - PROJECT SUMMARY Duchenne muscular dystrophy (DMD) is a progressive and devastating muscle disease, resulting from the absence of dystrophin. This leads to cell membrane instability, susceptibility to contraction-induced muscle damage, muscle cell death, and disability and early death of patients. Currently, there is no cure for DMD. Lipin1 is a phosphatidic acid (PA) phosphatase (PAP) enzyme that catalyzes diacylglycerol (DAG) biosynthesis. It is also the predominant lipin isoform in skeletal muscles. In addition to its enzymatic activity, lipin1 can regulate transcription. A recent publication from this lab identified a previously unknown role of lipin1 in promoting myocyte enhancer factor 2c (MEF2c) transcriptional activity via DAG signaling in skeletal muscle. Notably, our findings showed that loss of lipin1 leads to myopathy. Preliminary data also showed that lipin1 expression was dramatically reduced in the skeletal muscles of DMD patients and mdx (DMDmdx) mice, a mouse model for DMD. Strikingly, further data show that increasing lipin1 levels in mdx mice lessened muscle fiber degeneration, strengthened membrane integrity, and led to impressive gains in strength. Based on these novel findings, the central hypothesis of this proposal is that lipin1 overexpression ameliorates the dystrophic phenotype in DMD through its PAP activity and its ability to regulate transcription. This hypothesis will be tested via the following Specific Aims: 1) Assess the pathological and functional benefit of lipin1 overexpression in mdx:lipin1 transgenic mice in early and late stages of the disease; 2) Determine the therapeutic efficacy of AAV9-mediated systemic lipin1 gene delivery; and 3) Test the hypothesis that lipin1 regulates muscle membrane integrity through the transcriptional regulation of structural genes and through PAP activity. NIH Mission Relevance: DMD affects 15.9-19.5 individuals per 100,000 live births. Specifically, DMD patients often manifest disability around age 3-5, and many require a wheelchair before age 12. Progressive muscle weakness often results in early mortality around age 30. This research seeks to elucidate the role of lipin1 as a novel regulator to prevent dystrophic pathologies, and will determine whether lipin1 can serve as a target to re- establish membrane stability and restore muscle function. Such information is expected to have a transformative impact on the treatment of DMD, as well as open new avenues for the treatment of several clinically related conditions, such as rhabdomyolysis, age-related muscle loss, and other muscular dystrophies which share common features associated with decreased lipin1 expression.


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	2025	WRIGHT STATE UNIVERSITY	3640 COLONEL GLENN HWY	DAYTON	OH	45435	GREENE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	5	3/26/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $321,893 )
2025	2025	WRIGHT STATE UNIVERSITY	3640 COLONEL GLENN HWY	DAYTON	OH	45435	GREENE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	5	7/8/2025	NON-COMPETING CONTINUATION	$321,893
														Subtotal = $321,893

Issue Date FY: 2024 ( Subtotal = $353,102 )
2024	2024	WRIGHT STATE UNIVERSITY	3640 COLONEL GLENN HWY	DAYTON	OH	45435	GREENE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	4	5/21/2024	NON-COMPETING CONTINUATION	$353,102
														Subtotal = $353,102

Issue Date FY: 2023 ( Subtotal = $370,093 )
2023	2023	WRIGHT STATE UNIVERSITY	3640 COLONEL GLENN HWY	DAYTON	OH	45435	GREENE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	3	5/19/2023	NON-COMPETING CONTINUATION	$370,093
														Subtotal = $370,093

Issue Date FY: 2022 ( Subtotal = $372,238 )
2022	2022	WRIGHT STATE UNIVERSITY	3640 COLONEL GLENN HWY	DAYTON	OH	45435	GREENE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	6/10/2022	NON-COMPETING CONTINUATION	$372,238
														Subtotal = $372,238

Issue Date FY: 2021 ( Subtotal = $381,682 )
2021	2021	WRIGHT STATE UNIVERSITY	3640 COLONEL GLENN HWY	DAYTON	OH	45435	GREENE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	7/22/2021	NEW	$381,682
														Subtotal = $381,682

Grand Total All Awards = $1,799,008

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The Role of Lipin1 in Myofiber Stability and Integrity

Award Number: R01AR077574

ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/22/2021

PERIOD OF PERFORMANCE END DATE: 05/31/2027

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