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.

总体汇总 爱荷华州大学威尔斯通肌肉营养不良专门研究中心的总体目标是 （MDSRC）是对各种肌肉萎缩症进行研究，这些肌肉萎缩症是由异常的肌肉加工引起的。 肌营养不良聚糖蛋白（肌营养不良聚糖病）。中心将通过开展基本的 以及在营养不良聚糖病患者、患者来源的生物样品和小鼠模型中的转化研究。我们 MDSRC应用程序由两个项目和三个核心组成，所有项目都由研究人员指导， 在基础、转化和临床研究方面的卓越表现和合作记录。项目1 （坎贝尔）将研究细胞和分子机制，根据肌营养不良聚糖病， 评价α-肌营养不良蛋白聚糖（α-DG）基质聚糖长度与其层粘连蛋白结合之间的关系 在对照和肌营养不良聚糖病患者成纤维细胞和肌肉活检中的性质。其他研究将 定义由蛋白质-蛋白质和蛋白质-糖调节的基质聚糖合成的要求 交互.将利用肌营养不良聚糖病小鼠模型来确定新的病理生理机制 并确定改善肌肉功能所需的结构和层粘连蛋白结合特性。计划2 （马修斯）将完善FKRP相关肌营养不良聚糖病的自然史， 通过扩大评价患者的临床研究中心数量， 自然史研究，以更先进的临床严重程度的患者。非FKRP的延长随访 基因型将确定具有相似运动进展率的队列， 基因非特异性临床试验。血液或尿液中的候选蛋白质组学生物标志物用于全谱 将验证肌营养不良聚糖病基因型并将其与疾病状态相关。核心A（坎贝尔和摩尔）是 一个行政核心，将协调中心内外的活动，作为促进 一个互动和协作的研究环境，并参与肌肉萎缩症的研究患者。 核心B（摩尔），一个肌肉组织/细胞培养/诊断核心，将支持项目1和2，作为一个 国家组织和细胞培养资源的研究，提供专业的诊断测试，为广泛的 肌肉萎缩症，并保持所需的基础设施，以评估肌肉活检，以支持临床 审判最后，核心C（马修斯和坎贝尔）将协调我们的培训计划。在支持这 核心提供的奖学金将使每年两名医学生在中心进行研究， 与马修斯博士一起参与病人的护理，并提供基础科学培训的机会， 提供给博士后研究员和本科研究员。高度集成的内核和 该中心的项目将加快临床前转化研究的发现克里思， 建立一组肌营养不良聚糖病患者的临床试验准备。

项目成果

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

Miyoshi Muscular Dystrophy Due to Novel Splice Site Variants in DYSF Gene.

• DOI: 10.1177/2329048x221140298
• 发表时间: 2022-01
• 期刊: Child neurology open
• 作者: Bryant, Grace;Moore, Steven A;Nix, James S;Rice, Grace;Gokden, Murat;Veerapandiyan, Aravindhan
• 通讯作者: Veerapandiyan, Aravindhan

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

Large1 gene transfer in older myd mice with severe muscular dystrophy restores muscle function and greatly improves survival.

• DOI: 10.1126/sciadv.abn0379
• 发表时间: 2022-05-27
• 期刊: Science advances
• 影响因子: 13.6

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