The Role of Lipin1 in Myofiber Stability and Integrity

Lipin1 在肌纤维稳定性和完整性中的作用

• 批准号: 10455623
• 负责人: Hongmei Ren
• 金额: $ 37.22万
• 依托单位: WRIGHT STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-22 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10455623
• 关键词: Activities of Daily Living; Adult; Affect; Age; Anabolism; Attenuated; Cell Death; Cell membrane; Cessation of life; ChIP-seq; Clinical; Data; Diglycerides; Disease; Disease Progression; Disease model; Dose; Duchenne muscular dystrophy; Dystrophin; Enzymes; Gene Delivery; Gene Expression; Gene Expression Profile; Gene Transduction Agent; Genes; Genetic Transcription; Glycerophospholipids; Goals; Individual; Intramuscular; Lecithin; Lipids; Live Birth; Mediating; Membrane; Methods; Mission; Molecular; Morphology; Mus; Muscle; Muscle Cells; Muscle Contraction; Muscle Fibers; Muscle Weakness; Muscle function; Muscular Atrophy; Muscular Dystrophies; Myopathy; Pathologic; Pathology; Patients; Phase; Phenotype; Phosphatidate Phosphatase; Phosphatidic Acid; Phospholipids; Phosphoric Monoester Hydrolases; Play; Predisposition; Protein Isoforms; Public Health; Publications; Regenerative capacity; Regimen; Research; Resistance; Rhabdomyolysis; Role; Safety; Signal Transduction; Skeletal Muscle; Specificity; Stress; Structural Genes; Teenagers; Testing; Therapeutic; Transcription Coactivator; Transcriptional Regulation; Transgenic Mice; Transgenic Organisms; Treatment Efficacy; United States National Institutes of Health; Up-Regulation; Wheelchairs; Work; age-related muscle loss; aged; base; disability; effective therapy; exhaust; gene therapy; improved; intravenous administration; lipine; mRNA Expression; mdx mouse; micro-dystrophin; mortality; motor deficit; mouse model; muscle degeneration; muscle regeneration; mutant; myocyte-specific enhancer-binding-factor 2C; new therapeutic target; novel; overexpression; prevent; protective effect; protein expression; tool; transduction efficiency; young adult

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.

项目总结 Duchenne肌营养不良症(DMD)是一种进行性和破坏性的肌肉疾病，由 没有抗肌营养不良蛋白。这会导致细胞膜不稳定，对收缩诱导的肌肉敏感 损伤、肌细胞死亡，以及患者的残疾和过早死亡。目前，还没有治愈DMD的方法。 Lipin1是一种磷脂酸(PA)磷酸酶(PAP)，催化二酰甘油(DAG) 生物合成。它也是骨骼肌中主要的脂类异构体。除了它的酶活性， 脂蛋白1可以调节转录。该实验室最近发表的一篇论文发现了一个以前未知的脂蛋白1的作用 在骨骼肌中通过DAG信号促进肌细胞增强因子2c(MEF2C)的转录活性。 值得注意的是，我们的发现表明，脂蛋白1的丢失会导致肌病。初步数据还显示，脂蛋白1 在DMD患者和MDX(DMDmdx)小鼠的骨骼肌中表达显著减少，a DMD小鼠模型。令人惊讶的是，进一步的数据显示，增加mdx小鼠的脂蛋白1水平会减少肌肉。 纤维退化，加强了膜的完整性，并导致了令人印象深刻的强度增长。基于这些 新的发现，这一建议的中心假设是脂蛋白1的过度表达可以改善营养不良 DMD的表型通过其PAP活性和其调节转录的能力。这一假设将是 通过以下特定目的进行测试：1)评估脂类的病理和功能益处 MDX：脂蛋白1转基因小鼠在疾病早期和晚期的过度表达；2)确定 AAV9介导的系统脂蛋白1基因治疗效果；3)验证脂蛋白1的假说 通过结构基因的转录调节和通过 PAP活动。 NIH使命相关性：每100,000名活产儿中有15.9-19.5人感染DMD。具体来说，DMD患者 通常在3-5岁左右表现出残疾，许多人在12岁之前需要轮椅。进展性肌肉 虚弱通常会导致30岁左右的早期死亡。这项研究试图阐明脂蛋白1作为一种 防止营养不良病理的新型调节因子，并将决定Lipin1是否可以作为重新研究的靶点。 建立膜的稳定性，恢复肌肉功能。这样的信息预计会有一个 对DMD治疗的变革性影响，以及为治疗几种疾病开辟了新的途径 临床相关的情况，如横纹肌溶解、年龄相关性肌肉萎缩和其他肌肉营养不良 它们具有与脂蛋白1表达降低相关的共同特征。