Muscular Dystrophy Specialized Research Center

肌营养不良症专业研究中心

• 批准号: 10652506
• 负责人: KEVIN P. CAMPBELL
• 金额: $ 146.65万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-06-08 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10652506
• 关键词: Acceleration; Advisory Committees; Basic Science; Binding; Biochemical; Biological Markers; Biopsy; Blood; Cell Culture Techniques; Cells; Clinical; Clinical Research; Clinical Trials; Clinical Trials Design; Collaborations; Communication; Communities; Community Outreach; Cryopreservation; Development; Diagnosis; Diagnostic; Diagnostic tests; Disease; Dystroglycan; Environment; Fellowship; Fibroblasts; Functional disorder; Genes; Genotype; Goals; Human Resources; Infrastructure; Iowa; Laboratories; Laminin; Length; Measures; Medical Students; Mission; Molecular; Motor; Muscle; Muscle function; Muscular Dystrophies; Myoblasts; Myocardial tissue; Natural History; Neuromuscular Diseases; Patient Care; Patients; Pediatric Neurology; Postdoctoral Fellow; Property; Proteins; Proteomics; Qualifying; Regulation; Research; Research Personnel; Resource Sharing; Resources; Role; Scientist; Severities; Skeletal Muscle; Structure; Testing; Tissues; Training; Translating; Translational Research; Translations; United States National Institutes of Health; Universities; Urine; alpha Dystroglycan; cell repository; clinical care; clinical research site; clinical translation; clinical trial readiness; cohort; dystroglycanopathy; follow-up; fukutin related protein; graduate school; improved; insight; interest; medical schools; member; mouse model; muscle degeneration; next generation; novel; novel diagnostics; novel therapeutic intervention; patient engagement; pre-clinical; programs; rational design; receptor function; recruit; repository; skills; sugar; tissue culture; tissue/cell culture; training opportunity; undergraduate research; undergraduate student; user-friendly; web site

OVERALL SUMMARY The overall goal of the University of Iowa Wellstone Muscular Dystrophy Specialized Research Center (MDSRC) is to perform research on the various muscular dystrophies that arise from abnormal processing of the dystroglycan protein (dystroglycanopathies). The Center will achieve this overall goal by conducting basic and translational research in dystroglycanopathy patients, patient-derived biosamples, and mouse models. Our MDSRC application is composed of two projects and three cores, all of which are directed by investigators with a proven track record of excellence and collaboration in basic, translational and clinical research. Project 1 (Campbell) will investigate the cellular and molecular mechanisms that underly dystroglycanopathies by evaluating the relationship between α-dystroglycan (α-DG) matriglycan length and its laminin-binding properties in control and dystroglycanopathy patient fibroblasts and muscle biopsies. Additional studies will define the requirements for matriglycan synthesis as regulated by protein-protein and protein-sugar interactions. A dystroglycanopathy mouse model will be utilized to identify novel pathophysiologic mechanisms and determine the structure and laminin binding properties required to improve muscle function. Project 2 (Mathews) will refine the natural history of FKRP-related dystroglycanopathy derived from an established, unique cohort of patients by expanding the number of clinical sites evaluating patients and by extending the natural history study to patients with more advanced clinical severity. Extended follow up of non-FKRP genotypes will identify cohorts that share similar rates of motor progression who might be studied together in gene non-specific clinical trials. Candidate proteomic biomarkers in blood or urine for the full spectrum of dystroglycanopathy genotypes will be validated and related to disease status. Core A (Campbell and Moore) is an administrative core that will coordinate the activities within and outside the Center, as a means to promote an interactive and collaborative research environment, and to engage patients in muscular dystrophy research. Core B (Moore), a Muscle-Tissue/Cell-Culture/Diagnostics Core, will support Projects 1 and 2, serve as a national tissue and cell-culture resource for research, provide specialized diagnostic testing for a wide range of muscular dystrophies, and maintain the infrastructure needed to evaluate muscle biopsies in support of clinical trials. Finally, Core C (Mathews and Campbell) will coordinate our Training initiatives. Among the support this Core provides will be fellowships enabling two medical students per year to perform research in the Center and to participate in the care of patients alongside Dr. Mathews, with basic science training opportunities also provided to a postdoctoral fellow and an undergraduate research fellow. The highly integrated cores and projects of this Center will accelerate the tempo of discovery in preclinical translational research, and also establish the clinical-trial readiness of a cohort of dystroglycanopathy patients.

总结 爱荷华大学Wellstone肌营养不良症专业研究中心的总体目标 （MDSRC）是对因异常处理引起的各种肌肉营养不良的研究 多凝聚糖蛋白（多糖果病原体）。该中心将通过实现基本目标来实现这一总体目标 并翻译了对多糖肿瘤病患者，患者衍生的生物样本和小鼠模型的研究。我们的 MDSRC申请由两个项目和三个核心组成，所有这些都由调查员指导 基础，翻译和临床研究中卓越和协作的卓越记录。项目1 （坎贝尔）将调查基础上通过的细胞和分子机制，这些机制通过 评估α-Dystroglycan（α-DG）基质长度与其层粘连蛋白结合之间的关系 对照和肌营养不良的患者成纤维细胞和肌肉活检中的特性。其他研究还会 定义基质 - 蛋白质和蛋白质糖的要求 互动。将利用多糖瘤小鼠模型来识别新型的病理生理机制 并确定改善肌肉功能所需的结构和层粘连蛋白结合特性。项目2 （Mathews）将完善与FKRP相关的自然历史 通过扩大评估患者的临床部位的数量，并扩展 自然历史研究对患有更晚期临床严重程度的患者。非FKRP的延长随访 基因型将识别具有相似运动进度速率的同类型 基因非特异性临床试验。候选蛋白质组学生物标志物在血液或尿液中的全光谱 多糖肿瘤病基因型将得到验证并与疾病状况有关。核心A（坎贝尔和摩尔）是 将协调中心内部和外部活动的行政核心，以促进 互动和协作的研究环境，并吸引患者参与肌肉营养不良研究。 Core B（Moore）是一种肌肉组织/细胞培养/诊断核心，将支持项目1和2 用于研究的国家组织和细胞培养资源，为广泛的多种诊断测试提供了专门的诊断测试 肌肉营养不良，并维持评估肌肉活检所需的基础设施以支持临床 试验。最后，Core C（Mathews和Campbell）将协调我们的培训计划。在支持中 核心提供的将是奖学金，使每年两名医学生在中心进行研究， 为了与Mathews博士一起参加患者的护理，还提供基础科学培训机会 提供给博士后研究员和一位本科研究员。高度集成的核心和 该中心的项目将加速临床前翻译研究中发现的速度，也将 建立一群多糖肿瘤病患者的临床预审。

项目成果

Dystrophin and mini-dystrophin quantification by mass spectrometry in skeletal muscle for gene therapy development in Duchenne muscular dystrophy.

• DOI: 10.1038/s41434-021-00300-7
• 发表时间: 2022-11
• 期刊: GENE THERAPY
• 影响因子: 5.1
• 作者: Farrokhi, Vahid;Walsh, Jason;Palandra, Joe;Brodfuehrer, Joanne;Caiazzo, Teresa;Owens, Jane;Binks, Michael;Neelakantan, Srividya;Yong, Florence;Dua, Pinky;Le Guiner, Caroline;Neubert, Hendrik
• 通讯作者: Neubert, Hendrik

Cell surface glycan engineering reveals that matriglycan alone can recapitulate dystroglycan binding and function.

• DOI: 10.1038/s41467-022-31205-7
• 发表时间: 2022-06-24
• 期刊: Nature communications
• 影响因子: 16.6

Cytoplasmic body pathology in severe ACTA1-related myopathy in the absence of typical nemaline rods.

• DOI: 10.1016/j.nmd.2017.02.012
• 发表时间: 2017-06
• 期刊: Neuromuscular disorders : NMD
• 作者: Donkervoort S;Chan SHS;Hayes LH;Bradley N;Nguyen D;Leach ME;Mohassel P;Hu Y;Thangarajh M;Bharucha-Goebel D;Kan A;Ho RSL;Reyes CA;Nance J;Moore SA;Foley AR;Bönnemann CG
• 通讯作者: Bönnemann CG

Development and Validation of a Western Blot Method to Quantify Mini-Dystrophin in Human Skeletal Muscle Biopsies.

• DOI: 10.1208/s12248-022-00776-0
• 发表时间: 2022-12-20
• 期刊: The AAPS journal

Structural basis of laminin binding to the LARGE glycans on dystroglycan.

• DOI: 10.1038/nchembio.2146
• 发表时间: 2016-10
• 期刊: Nature chemical biology
• 影响因子: 14.8
• 作者: Briggs DC;Yoshida-Moriguchi T;Zheng T;Venzke D;Anderson ME;Strazzulli A;Moracci M;Yu L;Hohenester E;Campbell KP
• 通讯作者: Campbell KP