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：
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
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/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

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.

项目概要肌营养不良症心脏受累继发的心力衰竭是发病率和死亡率的主要驱动因素某些亚型肌营养不良症（包括杜氏肌营养不良症和贝克尔肌营养不良症）患者的死亡率营养不良。肌营养不良蛋白复合物将骨骼肌和心肌细胞骨架与细胞外细胞连接起来矩阵。编码肌营养不良蛋白复合物蛋白质的基因突变会导致肌营养不良症和心肌病。诱导多能干细胞（iPSC）可以从患者细胞中产生并分化进入心肌细胞（iPSC-CM）以提供患者/基因型特定的疾病模型。这些型号是在一定程度上受到其不成熟的限制，包括其抗肌营养不良蛋白复合物的表达。正确显示 iPSC-CM 中肌营养不良蛋白复合物的本质是，如果这个有前途的工具可用于测试新的肌营养不良继发的心肌病的治疗策略。该提案提出初步数据表明，微图案表面与熟化介质相结合可以改善 iPSC-CM 中肌营养不良蛋白复合物的表达和定位。其目的是充分表征 iPSC-CM 的肌营养不良蛋白复合物，并使用以下方法确定促进复合物成熟的条件微图案化的图案表面。使用该模型，肌肉营养不良症的几种治疗策略将使用来自具有 3 种不同肌肉亚型的患者的 iPSC 系进行评估影响肌营养不良蛋白复合物的肌营养不良症。该 NRSA 个人博士后奖学金旨在促进 Fullenkamp 博士作为一名医师科学家的发展。 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 是医师科学家培训计划 (PSTP) 和心血管疾病的参与者西北大学研究员。他已经完成了大部分临床培训，该奖学金将支持他的培训研究阶段。作为一名医师科学家，富伦坎普博士将受益于 McNally 博士的指导，他是国际公认的医学科学家，专长于心脏遗传学和肌营养不良症。西北大学强大的工程资源将让 Fullenkamp 博士将工程工具带入该项目，同时学习新技能分子和细胞生物学和遗传学。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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：
发表时间：
2021
期刊：
影响因子：
39.3
作者：
Fullenkamp, Dominic E;Puckelwartz, Megan J;McNally, Elizabeth M
通讯作者：
McNally, Elizabeth M

Genetic Variation in Enhancers Modifies Cardiomyopathy Gene Expression and Progression.

增强子的遗传变异改变心肌病基因表达和进展。

DOI：
发表时间：
2021-03-30
期刊：
影响因子：
37.8
作者：
Gacita, Anthony M;Fullenkamp, Dominic E;Ohiri, Joyce;Pottinger, Tess;Puckelwartz, Megan J;Nobrega, Marcelo A;McNally, Elizabeth M
通讯作者：
McNally, Elizabeth M