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Micropatterned surfaces for modeling muscular dystrophy-associated cardiomyopathy

用于模拟肌营养不良相关心肌病的微图案表面

基本信息

批准号：
10462478
负责人：
Dominic Edward Fullenkamp
金额：
$ 1.68万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-01 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10462478
关键词：
Actins Affect Annexin A6 Basement membrane Becker Muscular Dystrophy Binding Biomedical Engineering Cardiac Cardiac Myocytes Cardiomyopathies Cardiovascular Diseases Cell Differentiation process Cell Line Cell model Cells Clinical Complex Cytoskeleton Data Development Disease model Duchenne muscular dystrophy Dystroglycan Dystrophin Engineering Event Extracellular Matrix Extracellular Matrix Proteins Fellowship General Population Genes Genetic Genetic Medicine Glucocorticoids Growth Heart failure Human Individual Injury International Laminin Learning Limb-Girdle Muscular Dystrophies Link Mechanics Membrane Mentorship Modeling Molecular and Cellular Biology Morbidity - disease rate Mus Muscle Muscle Cells Muscular Dystrophies Muscular dystrophy cardiomyopathy Mutation Myocardium National Research Service Awards Participant Pathogenicity Patients Pattern Phase Phenotype Physicians Physiologic pulse Predisposition Proteins Public Health Recombinants Research Support Resources Sarcoglycans Sarcolemma Sarcomeres Scientist Secondary Myocardial Diseases Secondary to Signal Transduction Skeletal Muscle Skeletal muscle injury Steroid therapy Steroids Structure Subgroup Surface Testing Therapeutic Time Training Training Programs Treatment Efficacy Universities Up-Regulation Work alpha Dystroglycan base delta Sarcoglycan design effectiveness testing exon skipping extracellular fukutin related protein gamma Sarcoglycan genotyped patients improved in vitro Model induced pluripotent stem cell interest membrane model mortality mutant novel novel therapeutic intervention novel therapeutics skills stem cell technology tool treatment response

项目摘要

PROJECT SUMMARY Heart failure secondary to cardiac involvement of muscular dystrophy is a main driver of morbidity and mortality in patients with certain subtypes of muscular dystrophy, including Duchenne and Becker muscular dystrophy. The dystrophin complex connects the skeletal and cardiac muscle cytoskeleton to the extracelluar matrix. Mutations in genes that encode the proteins of the dystrophin complex cause muscular dystrophy and cardiomyopathy. Induced pluripotent stem cells (iPSCs) can be created from patient cells and differentiated into cardiomyocytes (iPSC-CMs) to provide patient/genotype specific models of disease. These models are somewhat limited by their immaturity, including in their expression of the dystrophin complex. Correct display of the dystrophin complex in iPSC-CMs is essentially if this promising tool is to useful in testing new therapeutic strategies for cardiomyopathy secondary to muscular dystrophy. This proposal presents preliminary data that demonstrates that micropatterned surfaces combined with maturation media can improve the expression and localization of the dystrophin complex in iPSC-CMs. It aims to fully characterize the dystrophin complex of iPSC-CMs and identify conditions that improve maturation of the complex using micropatterned patterned surfaces. Using this model, several therapeutic strategies for muscular dystrophy will be assessed using patient-derived iPSC lines from patients with 3 different subtypes of muscular of muscular dystrophy that affect the dystrophin complex. This NRSA individual postdoctoral fellowship is to facilitate Dr. Fullenkamp's development as a physician-scientist. Dr. Fullenkamp will carry out this work at the Center for Genetic Medicine at Northwestern University under the sponsorship of Dr. Elizabeth McNally. Dr. Fullenkamp is a participant in the Physician Scientist Training Program (PSTP) and a Cardiovascular Disease Fellow at Northwestern University. He has completed the majority of his clinical training and this fellowship will support the research phase of his training. As a physician-scientist, Dr. Fullenkamp will benefit uniquely from the mentorship of Dr. McNally who is an internationally recognized physician-scientist with specialization in cardiac genetics and muscular dystrophy. The strong engineering resources of Northwestern University will allow Dr. Fullenkamp to bring engineering tools to this project, while at the same time learning new skills in molecular and cellular biology and genetics.

项目总结继发于心脏受累的肌营养不良所致的心力衰竭是发病率和包括Duchenne和Becker肌肉营养不良在内的某些亚型肌营养不良患者的死亡率营养不良。肌营养不良蛋白复合体将骨骼肌和心肌细胞骨架连接到细胞外矩阵。编码营养不良蛋白复合体蛋白质的基因突变会导致肌肉营养不良和心肌病。诱导多能干细胞(IPSCs)可以从患者细胞中产生并分化转化为心肌细胞(IPSC-CMS)，以提供患者/基因型特定的疾病模型。这些型号是在某种程度上受到它们不成熟的限制，包括在它们对dystrophin复合体的表达方面。正确显示在IPSC-CMS中的抗肌营养不良蛋白复合体的研究基本上是如果这个有前途的工具在测试新的肌营养不良继发心肌病的治疗策略。这份提案提出了初步数据表明，与成熟介质相结合的微图案表面可以改善抗肌营养不良蛋白复合体在IPSC-CMS中的表达和定位。它的目的是充分描述 IpSC-CMS的抗肌营养不良蛋白复合体，并鉴定促进该复合体成熟的条件微图案化的表面。利用这个模型，肌营养不良症的几种治疗策略将使用患者来源的IPSC系进行评估，这些患者来自患有3种不同肌肉亚型的患者影响肌营养不良蛋白复合体的肌营养不良症。这个NRSA个人博士后奖学金是为了促进富伦坎普博士作为内科科学家的发展。富伦坎普博士将在西北大学遗传医学中心，由伊丽莎白·麦克纳利博士赞助。Dr。富伦坎普是医生科学家培训计划(PSTP)的参与者，也是一种心血管疾病西北大学研究员。他已经完成了大部分的临床训练，这笔奖学金将支持他培训的研究阶段。作为一名内科科学家，富伦坎普博士将受益于麦克纳利博士的指导，他是国际公认的内科科学家，专门从事心脏遗传学和肌肉营养不良。西北大学强大的工程资源将允许Fullenkamp博士将工程工具带到这个项目中，同时在分子、细胞生物学和遗传学。