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

• 批准号: 10410238
• 负责人: Dominic Edward Fullenkamp
• 金额: $ 3.93万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 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/10410238
• 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

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.

项目摘要 继发于肌营养不良心脏受累的心力衰竭是发病率的主要驱动因素， 某些肌营养不良亚型患者的死亡率，包括Duchenne和Becker肌营养不良 营养不良肌营养不良蛋白复合体连接骨骼肌和心肌细胞骨架与细胞外基质， 矩阵编码肌营养不良蛋白复合物蛋白质的基因突变引起肌营养不良， 心肌病诱导多能干细胞（iPSC）可以从患者细胞中产生并分化 转化为心肌细胞（iPSC-CM）以提供患者/基因型特异性疾病模型。这些模型 由于它们的不成熟性，包括抗肌萎缩蛋白复合物的表达，它们的能力受到一定的限制。正确显示 iPSC-CM中肌营养不良蛋白复合物的重要性在于， 肌营养不良继发心肌病的治疗策略。该提案提出 初步数据表明，微图案化表面与成熟介质相结合， iPSC-CM中肌养蛋白复合物的表达和定位。它旨在充分描述 本发明涉及iPSC-CM的肌营养不良蛋白复合物，并使用 微图案化的图案化表面。使用这个模型，几种治疗策略，肌营养不良症 将使用来自患有3种不同肌萎缩症亚型的患者的患者来源的iPSC系进行评估。 影响肌营养不良蛋白复合体的肌肉萎缩症。这个NRSA个人博士后奖学金是为了 促进Fullenkamp博士成为一名科学家Fullenkamp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。博士 Fullenkamp是医生科学家培训计划（PSTP）和心血管疾病的参与者 西北大学的研究员他已经完成了大部分的临床培训，这个奖学金将 支持他训练的研究阶段作为一名医生科学家，Fullenkamp博士将受益于 McNally博士的指导，他是一位国际公认的医学科学家， 心脏遗传学和肌肉萎缩症。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，同时学习新的技能， 分子和细胞生物学和遗传学。

项目成果

Genome-wide association for heart failure: from discovery to clinical use.

心力衰竭的全基因组关联：从发现到临床应用。

• DOI: 10.1093/eurheartj/ehab172
• 发表时间: 2021
• 期刊: European heart journal
• 影响因子: 39.3
• 作者: Fullenkamp,DominicE;Puckelwartz,MeganJ;McNally,ElizabethM
• 通讯作者: McNally,ElizabethM

Genetic Variation in Enhancers Modifies Cardiomyopathy Gene Expression and Progression.

• DOI: 10.1161/circulationaha.120.050432
• 发表时间: 2021-03-30
• 期刊: Circulation
• 影响因子: 37.8
• 作者: Gacita AM;Fullenkamp DE;Ohiri J;Pottinger T;Puckelwartz MJ;Nobrega MA;McNally EM
• 通讯作者: McNally EM