Understanding the mechanism and role of cell membrane repair in Miyoshi Myopathy

了解细胞膜修复在三好肌病中的机制和作用

基本信息

批准号：
10188422
负责人：
JYOTI K JAISWAL
金额：
$ 37.11万
依托单位：
CHILDREN'S RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-07-02 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10188422
关键词：
Address Antioxidants B-Lymphocytes Cell Survival Cell membrane Cells Cholesterol Creatine Kinase Cytoskeleton DYSF gene Development Disease Endosomes Enzymes Excision Exocytosis F-Actin Generations Genes Human Injury Intervention Knowledge Limb-Girdle Muscular Dystrophies Lipid Bilayers Lipids Liver Lysosomes Maintenance Mediating Membrane Membrane Fusion Membrane Lipids Membrane Proteins Miyoshi myopathy Monitor Mus Muscle Muscle Cells Muscle Fibers Muscular Dystrophies Mutation Normal Cell Oxides Patients Pharmaceutical Preparations Process Proteins Recombinants Role Sarcolemma Serum Site Skeletal Muscle Sphingomyelinase Sphingomyelins Testing Therapeutic Therapeutic Intervention Vitamin E Vitamins acid sphingomyelinase cell injury combinatorial dysferlinopathies extracellular extracellular vesicles improved in vivo injured injury and repair insight live cell imaging mouse model novel novel therapeutics oxidation oxidized lipid pre-clinical preclinical efficacy prevent repaired

项目摘要

Summary Many muscular dystrophies are caused by mutation in proteins that compromise the stability and integrity of the muscle sarcolemma, which results in high serum level of muscle enzymes such as Creatine Kinase. Understanding the mechanism by which healthy myofibers maintain their sarcolemmal integrity would enable development of new therapies for these muscular dystrophies. Miyoshi myopathy (MM) and limb girdle muscular dystrophy (LGMD) 2B, caused by mutations in dysferlin gene are such diseases. We have identified that loss of sarcolemmal integrity in LGMD2B muscle fibers is due to the delay in fusion of lysosome with the injured sarcolemma. This causes a delay in injury-triggered secretion of the lysosomal enzyme acid sphingomyelinase. Providing extracellular sphingomyelinase reverses the repair deficit and offers a potential therapy for LGMD2B. However, the mechanism by which alteration in sphingomyelin and other cell membrane lipids facilitates repair of injured muscle cell membranes has not been fully elucidated. This proposal aims to identify how lipids and lipid modifying enzymes such as acid sphingomyelinase facilitate maintenance of sarcolemmal integrity and facilitate repair of injured sarcolemma. We will achieve this by visualizing and modifying lipid composition of healthy muscle cell membrane and assess their effect on sarcolemmal integirty. We will also assess how lipids respond are altered in the LGMD2B patient and mouse muscle cells to identify potential therapeutic interventions to address these alterations. One such intervention we have established is the use of acid sphingomyelinase and we will evaluate its preclinical therapeutic potential for LGMD2B. These studies will not only help understand the role of lipids in maintenance of sarcolemmal integrity, but also provide insight into developing novel therapies for muscular dystrophies that move beyond targeting the proteins to also targeting the sarcolemmal lipids.

概括许多肌肉营养不良是由蛋白质突变引起的，这些蛋白质会损害稳定性和完整性肌肉肌膜出现，导致高血清肌肉水平的肌肉酶，例如肌酸激酶。了解健康的肌纤维保持其肌肉完整性的机制将实现开发这些肌肉营养不良的新疗法。 Miyoshi肌病（MM）和肢体腰带由Dysferlin基因突变引起的肌肉营养不良（LGMD）2B是这种疾病。我们已经确定了 LGMD2B肌肉纤维中肌膜完整性的丧失是由于溶酶体融合的延迟受伤的肌体育。这会导致溶酶体酶的损伤触发的分泌延迟鞘磷脂酶。提供细胞外鞘磷脂酶可以逆转修复缺陷，并提供潜力 LGMD2B的治疗。但是，鞘磷脂和其他细胞膜改变的机制脂质促进了受伤的肌肉细胞膜的修复，尚未完全阐明。该建议旨在确定脂质和脂质修饰酶如何促进酸鞘磷脂酶促进维持肌膜完整性并促进受伤的肌膜的修复。我们将通过可视化和修饰健康肌肉细胞膜的脂质组成，并评估其对肌膜不动的作用。我们还将评估LGMD2B患者和小鼠肌肉细胞的脂质反应如何改变解决这些改变的潜在治疗干预措施。我们确定的一种这样的干预是使用酸鞘磷脂酶，我们将评估其在LGMD2B的临床前治疗潜力。这些研究不仅将有助于了解脂质在维持肌肉完整性中的作用，而且还提供深入了解开发新型肌肉营养不良的新疗法，这些肌营养不良超出靶向蛋白质还针对肌膜脂质。

项目成果

期刊论文数量（41）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Mitochondrial dysfunction and consequences in calpain-3-deficient muscle.

DOI：
10.1186/s13395-020-00254-1
发表时间：
2020-12-11
期刊：
Skeletal muscle
影响因子：
4.9
作者：
Jahnke VE;Peterson JM;Van Der Meulen JH;Boehler J;Uaesoontrachoon K;Johnston HK;Defour A;Phadke A;Yu Q;Jaiswal JK;Nagaraju K
通讯作者：
Nagaraju K

Single-cell and spatial transcriptomics identify a macrophage population associated with skeletal muscle fibrosis.

DOI：
10.1126/sciadv.add9984
发表时间：
2023-07-07
期刊：
Science advances
影响因子：
13.6
作者：
通讯作者：

The macrophage as a Trojan horse for antisense oligonucleotide delivery.

巨噬细胞作为反义寡核苷酸递送的特洛伊木马。

DOI：
10.1080/14728222.2018.1482279
发表时间：
2018-06
期刊：
Expert opinion on therapeutic targets
影响因子：
5.8
作者：
Novak JS;Jaiswal JK;Partridge TA
通讯作者：
Partridge TA

S100A11 is required for efficient plasma membrane repair and survival of invasive cancer cells.

DOI：
10.1038/ncomms4795
发表时间：
2014-05-08
期刊：
NATURE COMMUNICATIONS
影响因子：
16.6
作者：
Jaiswal, Jyoti K.;Lauritzen, Stine P.;Scheffer, Luana;Sakaguchi, Masakiyo;Bunkenborg, Jakob;Simon, Sanford M.;Kallunki, Tuula;Jaattela, Marja;Nylandsted, Jesper
通讯作者：
Nylandsted, Jesper

Early Endosomes Undergo Calcium-Triggered Exocytosis and Enable Repair of Diffuse and Focal Plasma Membrane Injury.