Physiologic stress in advanced tissue culture models of cardiomyopathy

心肌病高级组织培养模型中的生理应激

基本信息

批准号：
10592151
负责人：
Dominic Edward Fullenkamp
金额：
$ 16.41万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-12-15 至 2027-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10592151
关键词：
3-Dimensional Affect Annexin A6 Arrhythmia Award Biological Markers Biology Biomedical Engineering CRISPR/Cas technology Cardiac Cardiac Myocytes Cardiology Cardiomyopathies Cardiovascular system Cell Line Cell Nucleus Cell membrane Cells Clinical Code Collaborations Complex Data Defect Development Development Plans Dilated Cardiomyopathy Disease Doctor of Philosophy Duchenne muscular dystrophy Dystrophin Effectiveness Electrophysiology (science)Engineering Ensure Extracellular Matrix Genes Genetic Genetic Diseases Genetic Medicine Heart Heart failure Human Hydrogels Injury Intermediate Filaments Lamin Type A Lead Left Ventricular Dysfunction Life Link Measurement Measures Mechanical Stress Mechanics Membrane Mentors Mentorship Methods Modeling Morbidity - disease rate Muscular Dystrophies Mutation Myocardium Nuclear Envelope Nuclear Lamina Output Pathologic Patients Phenotype Physicians Physiological Play Predisposition Proteins Recombinants Research Research Personnel Role Sarcomeres Scientist Signal Transduction Signaling Protein Skeletal Muscle Stress Structural Protein System Technology Testing Therapeutic Effect Tissue constructs Tissues Training Troponin Universities Work bench to bedside cardiac tissue engineering career development clinical translation clinically relevant comparison control disease-causing mutation drug testing electrical measurement exon skipping experience flexibility flexible electronics gene therapy improved individualized medicine induced pluripotent stem cell induced pluripotent stem cell derived cardiomyocytes inhibitor interest male monolayer mortality mutant novel novel therapeutic intervention novel therapeutics protein complex prototype response stressor therapeutic evaluation tissue culture transmission process two-dimensional

项目摘要

PROJECT SUMMARY/ABSTRACT Multiple forms of muscular dystrophy are characterized by cardiac involvement which can be life-threatening, including Duchenne muscular dystrophy (DMD) and LMNA-related muscular dystrophy. These diseases are caused by mutations in DMD and LMNA, respectively. Heart failure is a leading cause of morbidity and mortality in these diseases. Physiologic mechanical stress in skeletal and cardiac muscle is a main driver of disease in these forms of muscular dystrophy. In addition, cardiac arrhythmias, disproportionate to left ventricular dysfunction, are prominent in LMNA-related disease. New therapeutic strategies, such as exon skipping, gene therapy, and CRISPR-Cas9 gene editing, are in development or have been approved for these diseases. Patient-specific induced pluripotent stem cells can be created and differentiated into cardiomyocytes (iPSC-CMs), offering the opportunity to study patient-specific mutations and test therapeutics in the dish. However, iPSC-CMs are limited by tissue immaturity, non-physiologic stressors, and non-physiologic outputs. Engineered heart tissues are created by seeding iPSC-CMs in a hydrogel matrix that is supported by flexible posts. With these tissue constructs, a more advanced degree of cellular maturation can be achieved, and outputs such as contraction velocity and amplitude can be readily determined. Specific Aim 1 of this K08 award aims assess the effect of physiologic mechanical stress on iPSC-CMs. Specific Aim 2 will improve the assessment of arrhythmogenic potential in novel engineered heart tissue constructs using patient-derived iPSC-CMs harboring DMD and LMNA mutations. Novel therapeutics for both disease entities will be assessed. Preliminary data is presented that demonstrates increased susceptibility of DMD iPSC-CMs to mechanical stress and mitigation of this phenotype by a novel therapeutic. An engineered heart tissue prototype is presented that will allow for the direct electrophysiologic interrogation of these tissues. We expect this prototype, which will allow for more uniform pacing, will be useful, especially in characterizing novel therapeutic effects on LMNA iPSC-CMs. This K08 will support the career development plan for the PI, Dominic Fullenkamp MD PhD, who received his graduate training in biomedical engineering and is physician-scientist cardiologist. Dr. Fullenkamp's long-term objective is to become an independent investigator as a physician scientist at the interface of cardiovascular biology and engineering, and use this interface to test novel therapeutics. In addition to the research proposed, Dr. Fullenkamp aims to use this award to further develop his training in cardiovascular biology under the mentorship of Elizabeth McNally MD PhD and Alfred George MD, two experienced and collaborative mentors, at Northwestern University. His development plan will be supported by internal and external coursework and clinical activity that directly correlates with his research interests.

项目摘要/摘要 Multiple forms of muscular dystrophy are characterized by cardiac involvement which can be life-threatening, including Duchenne muscular dystrophy (DMD) and LMNA-related muscular dystrophy. These diseases are caused by mutations in DMD and LMNA, respectively. Heart failure is a leading cause of morbidity and mortality in these diseases. Physiologic mechanical stress in skeletal and cardiac muscle is a main driver of disease in these forms of muscular dystrophy. In addition, cardiac arrhythmias, disproportionate to left ventricular dysfunction, are prominent in LMNA-related disease. New therapeutic strategies, such as exon skipping, gene therapy, and CRISPR-Cas9 gene editing, are in development or have been approved for these 疾病。 Patient-specific induced pluripotent stem cells can be created and differentiated into cardiomyocytes (iPSC-CMs), offering the opportunity to study patient-specific mutations and test therapeutics in the dish. However, iPSC-CMs are limited by tissue immaturity, non-physiologic stressors, and non-physiologic outputs. Engineered heart tissues are created by seeding iPSC-CMs in a hydrogel matrix that is supported by flexible 帖子。 With these tissue constructs, a more advanced degree of cellular maturation can be achieved, and outputs such as contraction velocity and amplitude can be readily determined. Specific Aim 1 of this K08 award aims assess the effect of physiologic mechanical stress on iPSC-CMs. Specific Aim 2 will improve the assessment of arrhythmogenic potential in novel engineered heart tissue constructs using patient-derived iPSC-CMs harboring DMD and LMNA mutations. Novel therapeutics for both disease entities will be assessed. Preliminary data is presented that demonstrates increased susceptibility of DMD iPSC-CMs to mechanical stress and mitigation of this phenotype by a novel therapeutic. An engineered heart tissue prototype is presented that will allow for the direct electrophysiologic interrogation of these tissues. We expect this prototype, which will allow for more uniform pacing, will be useful, especially in characterizing novel therapeutic effects on LMNA iPSC-CMs. This K08 will support the career development plan for the PI, Dominic Fullenkamp MD PhD, who received his graduate training in biomedical engineering and is physician-scientist cardiologist. Dr. Fullenkamp's long-term objective is to become an independent investigator as a physician scientist at the interface of cardiovascular biology and engineering, and use this interface to test novel therapeutics.在 addition to the research proposed, Dr. Fullenkamp aims to use this award to further develop his training in cardiovascular biology under the mentorship of Elizabeth McNally MD PhD and Alfred George MD, two experienced and collaborative mentors, at Northwestern University. His development plan will be supported by internal and external coursework and clinical activity that directly correlates with his research interests.