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: 10642806
• 负责人: Hongmei Ren
• 金额: $ 37.01万
• 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/10642806
• 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; 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; 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.

项目摘要 杜氏肌营养不良症（DMD）是一种进行性和破坏性的肌肉疾病，由 缺乏抗肌萎缩蛋白。这导致细胞膜不稳定，易受肌肉收缩的影响 损伤、肌细胞死亡、残疾和患者早死。目前，DMD还没有治愈方法。 Lipin 1是一种磷脂酸（PA）磷酸酶（PAP），催化甘油二酯（DAG） 生物合成它也是骨骼肌中主要的脂质异构体。除了其酶活性之外， lipin 1可以调节转录。该实验室最近发表的一篇文章确定了lipin 1以前未知的作用 在骨骼肌中通过DAG信号促进肌细胞增强因子2c（MEF 2c）的转录活性。 值得注意的是，我们的研究结果表明，lipin 1的损失导致肌病。初步数据还显示，lipin 1 在DMD患者和mdx（DMDmdx）小鼠的骨骼肌中， DMD的小鼠模型。引人注目的是，进一步的数据表明，mdx小鼠体内lipin 1水平的增加会减少肌肉 纤维变性，加强膜的完整性，并导致令人印象深刻的收益的力量。基于这些 新的发现，该建议的中心假设是lipin 1过表达改善了营养不良的 通过其PAP活性和其调节转录的能力在DMD表型中起作用。这一假设将是 通过以下特定目的进行测试：1）评估lipin的病理和功能益处1 mdx：lipin 1转基因小鼠在疾病早期和晚期的过度表达; 2）确定mdx：lipin 1转基因小鼠在疾病早期和晚期的过度表达。 AAV 9介导的全身性脂蛋白1基因递送的治疗功效;和3）检验脂蛋白1基因递送的假设， 通过结构基因的转录调节和 PAP活性。 NIH使命相关性：DMD影响每10万例活产15.9-19.5例。特别是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。渐进式肌肉 虚弱往往导致30岁左右的过早死亡。这项研究旨在阐明lipin 1作为一种 一种新的调节剂，以防止营养不良的病理，并将确定脂蛋白1是否可以作为目标，以重新 建立膜稳定性并恢复肌肉功能。预计此类信息将具有 对DMD治疗的变革性影响，以及为治疗几种 临床相关疾病，如横纹肌溶解症、年龄相关性肌肉损失和其他肌营养不良症 其具有与lipin 1表达降低相关的共同特征。

项目成果

Tacrolimus induces fibroblast-to-myofibroblast transition via a TGF-β-dependent mechanism to contribute to renal fibrosis.

他克莫司通过 TGF-β 依赖性机制诱导成纤维细胞向肌成纤维细胞的转变，从而促进肾纤维化。

• DOI: 10.1152/ajprenal.00226.2022
• 发表时间: 2023
• 期刊: American journal of physiology. Renal physiology
• 作者: Ume,AdakuC;Wenegieme,TaraY;Shelby,JennaeN;Paul-Onyia,ChiagozieDB;Waite3rd,AstonMJ;Kamau,JohnK;Adams,DanielleN;Susuki,Keiichiro;Bennett,EricS;Ren,Hongmei;Williams,ClintoriaR
• 通讯作者: Williams,ClintoriaR

Automated Image Analysis Pipeline Development to Monitor Disease Progression in Muscular Dystrophy Using Cell Profiler.

• DOI: 10.26502/ami.936500115
• 发表时间: 2023
• 期刊: Archives of microbiology & immunology