Micropatterned surfaces for modeling muscular dystrophy-associated cardiomyopathy

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。

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.