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.

项目概要 杜氏肌营养不良症 (DMD) 是一种进行性、破坏性的肌肉疾病，由以下原因引起： 缺乏肌营养不良蛋白。这导致细胞膜不稳定，对收缩引起的肌肉敏感 损伤、肌肉细胞死亡以及患者残疾和过早死亡。目前，DMD 尚无治愈方法。 Lipin1 是一种磷脂酸 (PA) 磷酸酶 (PAP)，可催化二酰甘油 (DAG) 生物合成。它也是骨骼肌中主要的脂质亚型。除了其酶活性外， lipin1可以调节转录。该实验室最近发表的一篇文章确定了 lipin1 的先前未知的作用 通过骨骼肌中的 DAG 信号传导促进肌细胞增强因子 2c (MEF2c) 转录活性。 值得注意的是，我们的研究结果表明，lipin1 的缺失会导致肌病。初步数据还表明，lipin1 DMD 患者和 mdx (DMDmdx) 小鼠骨骼肌中的表达显着降低， DMD 小鼠模型。引人注目的是，进一步的数据表明，增加 mdx 小鼠的 lipin1 水平会减少肌肉 纤维变性，膜完整性增强，强度显着提高。基于这些 新颖的发现，该提案的中心假设是 lipin1 过度表达可改善营养不良 DMD 中的表型通过其 PAP 活性及其调节转录的能力来确定。这个假设将是 通过以下具体目标进行测试： 1) 评估 lipin1 的病理和功能益处 mdx:lipin1 转基因小鼠在疾病早期和晚期过度表达； 2）确定 AAV9 介导的全身性 lipin1 基因传递的治疗效果； 3) 检验 lipin1 的假设 通过结构基因的转录调节和通过 巴氏活动。 NIH 使命相关性：每 100,000 名活产婴儿中有 15.9-19.5 人受到 DMD 影响。具体而言，DMD 患者 通常在 3-5 岁左右出现残疾，许多人在 12 岁之前需要轮椅。 渐进性肌肉 虚弱常常导致 30 岁左右过早死亡。这项研究旨在阐明 lipin1 作为 预防营养不良病理的新型调节剂，并将确定 lipin1 是否可以作为重新调节的靶点 建立膜稳定性并恢复肌肉功能。预计此类信息将具有 对 DMD 治疗产生变革性影响，并为多种疾病的治疗开辟新途径 临床相关病症，例如横纹肌溶解症、年龄相关性肌肉丧失和其他肌营养不良症 它们具有与 lipin1 表达减少相关的共同特征。