The role of TGF beta pathway dysregulation in pathogenesis of collagen VI-related muscular dystrophy

TGFβ途径失调在胶原VI相关性肌营养不良症发病机制中的作用

• 批准号: 10630309
• 负责人: Payam Mohassel
• 金额: $ 23.41万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10630309
• 关键词: Affinity; Alleles; Animal Model; Area; Atrophic; Attention; Bethlem Myopathy; Binding; Binding Proteins; Biological Assay; Biopsy; Blinded; COL6A1; COL6A2; COL6A3; Cells; Clinical Research; Collagen Gene; Collagen Type VI; Complex; Confocal Microscopy; Data; Defect; Disease; Disease model; Excretory function; Extracellular Matrix; Extracellular Matrix Proteins; Fibroblasts; Fibrosis; Fluorescence Resonance Energy Transfer; Funding; Future; Genes; Goals; Growth Factor; Histologic; Human; Immunoprecipitation; In Vitro; Injury; Intervention; Investigation; Laboratories; Luciferases; MFAP1 gene; Medicine; Microscopy; Modeling; Monoclonal Antibodies; Mus; Muscle; Muscle Proteins; Muscle Weakness; Muscular Atrophy; Muscular Dystrophies; Mutation; Myopathy; Natural regeneration; Outcome Measure; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Physiological; Proteins; Randomized; Regenerative pathway; Regenerative response; Regulation; Reporter; Research Project Grants; Resolution; Role; Scientist; Severity of illness; Signal Pathway; Signal Transduction; Skeletal Muscle; Small Interfering RNA; Source; Standardization; Techniques; Tertiary Protein Structure; Testing; Training; Transforming Growth Factor beta; Translational Research; Translations; Ullrich Congenital Muscular Dystrophy; United States National Institutes of Health; Up-Regulation; career; design; disability; disease natural history; drug candidate; effectiveness testing; efficacy study; extracellular; gel electrophoresis; inhibitor; mouse model; muscle regeneration; neuromuscular; novel; postnatal; preclinical study; prospective; receptor; recruit; response to injury; skills; therapeutic target; transcriptome

Project Summary/Abstract:     Mutations in collagen VI cause a spectrum of muscle disease ranging from severe Ullrich congenital muscular  dystrophy to the milder Bethlem myopathy.  The three protein components of collagen VI encoded by COL6A1,  COL6A2, and COL6A3, undergo extensive assembly after translation before being excreted and incorporated  into the extracellular matrix (ECM). Collagen VI is an integral component of the ECM, making collagen VI  related dystrophies prototypical disorders of the muscle ECM.  However, how these mutations result in muscle  weakness, atrophy, degeneration and fibrosis remains unknown and no specific therapies are available that  can alter the natural history of this disease. In this study, we propose to characterize the histologic and  functional changes in skeletal muscle of a new mouse model of collagen VI related dystrophies with  homozygous deletion of the Col6a2 alleles, paying special attention to dysregulation of growth factor pathways  associated with these changes. For the interventional phase of this study, we propose to test effectiveness of  medications in treating the manifestation of disease in this animal model. This study will also provide funding  for in depth training of an early career clinician scientist with prior neuromuscular medicine training to develop  laboratory techniques and scientific skills to conduct translational research and pre-­clinical studies of animal  models of muscular dystrophies.

项目概要/摘要：   VI型胶原蛋白的突变会导致一系列肌肉疾病，从严重的乌尔里希先天性肌肉疾病， 由COL 6A 1编码的胶原VI的三种蛋白质组分， COL 6A 2和COL 6A 3在翻译后进行大量组装，然后被排泄和整合 胶原蛋白VI是ECM的组成成分，使得胶原蛋白VI在细胞外基质（ECM）中形成。 相关营养不良的肌肉ECM的原型疾病。然而，这些突变如何导致肌肉 虚弱、萎缩、变性和纤维化仍然是未知的，并且没有可用的特定疗法， 在这项研究中，我们提出了组织学特征， 胶原VI相关营养不良的新小鼠模型的骨骼肌功能变化， Col 6a 2等位基因的纯合缺失，特别注意生长因子途径的失调 对于本研究的干预阶段，我们建议测试 药物治疗疾病的表现在这个动物模型。这项研究还将提供资金 对一名早期职业临床医生科学家进行深入培训，并接受过神经肌肉医学培训， 实验室技术和科学技能，以进行转化研究和动物的临床前研究 肌肉萎缩症的模型。

项目成果

Recurring homozygous ACTN2 variant (p.Arg506Gly) causes a recessive myopathy.

复发性纯合 ACTN2 变异 (p.Arg506Gly) 会导致隐性肌病。

• DOI: 10.1002/acn3.51983
• 发表时间: 2024
• 期刊: Annals of clinical and translational neurology
• 影响因子: 5.3
• 作者: Donkervoort,Sandra;Mohassel,Payam;O'Leary,Melanie;Bonner,DevonE;Hartley,Taila;Acquaye,Nicole;Brull,Astrid;Mozaffar,Tahseen;Saporta,MarioA;Dyment,DavidA;Sampson,JacindaB;Pajusalu,Sander;Austin-Tse,Christina;Hurth,Kyle;Cohen,
• 通讯作者: Cohen,

The SPTLC1 p.S331 mutation bridges sensory neuropathy and motor neuron disease and has implications for treatment.

• DOI: 10.1111/nan.12842
• 发表时间: 2022-12
• 期刊: NEUROPATHOLOGY AND APPLIED NEUROBIOLOGY
• 影响因子: 5
• 作者: Fiorillo, Chiara;Capodivento, Giovanna;Geroldi, Alessandro;Tozza, Stefano;Moroni, Isabella;Mohassel, Payam;Cataldi, Matteo;Campana, Chiara;Morando, Simone;Panicucci, Chiara;Pedemonte, Marina;Brolatti, Noemi;Siliquini, Sabrina;Traverso, Monica;Baratto, Serena;Debellis, Doriana;Magri, Stefania;Prada, Valeria;Bellone, Emilia;Salpietro, Vincenzo;Donkervoort, Sandra;Gable, Kenneth;Gupta, Sita D.;Dunn, Teresa M.;Bonnemann, Carsten G.;Taroni, Franco;Bruno, Claudio;Schenone, Angelo;Mandich, Paola;Nobbio, Lucilla;Nolano, Maria
• 通讯作者: Nolano, Maria

SPTLC1 variants associated with ALS produce distinct sphingolipid signatures through impaired interaction with ORMDL proteins.

• DOI: 10.1172/jci161908
• 发表时间: 2022-09-15
• 期刊: JOURNAL OF CLINICAL INVESTIGATION
• 影响因子: 15.9
• 作者: Lone, Museer A.;Aaltonen, Mari J.;Zidell, Aliza;Pedro, Helio F.;Saute, Jonas A. Morales;Mathew, Shalett;Mohassel, Payam;Bonnemann, Carsten G.;Shoubridge, Eric A.;Hornemann, Thorsten
• 通讯作者: Hornemann, Thorsten

Rycal S48168 (ARM210) for RYR1-related myopathies: a phase one, open-label, dose-escalation trial.

Rycal S48168 (ARM210) 用于治疗 RYR1 相关肌病：一期、开放标签、剂量递增试验。

• DOI: 10.1016/j.eclinm.2024.102433
• 发表时间: 2024
• 期刊: EClinicalMedicine
• 影响因子: 15.1
• 作者: Todd,JoshuaJ;Lawal,TokunborA;Chrismer,IreneC;Kokkinis,Angela;Grunseich,Christopher;Jain,MinalS;Waite,MelissaR;Biancavilla,Victoria;Pocock,Shavonne;Brooks,Kia;Mendoza,ChristopherJ;Norato,Gina;Cheung,Ken;Riekhof,Willa;Varma
• 通讯作者: Varma