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Understanding the Transcriptional Networks and Physiologic Adaptations Governing the Clinical Manifestations of Duchenne Muscular Dystrophy

了解控制杜氏肌营养不良症临床表现的转录网络和生理适应

基本信息

批准号：
10672427
负责人：
Bayardo Isidore Garay
金额：
$ 5.27万
依托单位：
UNIVERSITY OF MINNESOTA
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：
2020-07-27 至 2024-07-26
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10672427
关键词：
Action Potentials Acute Address Affect Age Animal Model Biological Assay Biopsy Calcium Signaling Cardiac Cardiac Myocytes Cell Differentiation process Cell Line Cell Membrane Permeability Cell membrane Cell physiology Cells Cellular biology Chemicals Chronic Clinical Data Development Discipline Disease Disease Progression Doctor of Philosophy Dose Duchenne muscular dystrophy Dystrophin Electrophysiology (science)Evolution Functional disorder Gene Expression Profile Genes Genetic Transcription Goals Heart failure Heterogeneity Human Impairment In Vitro Ion Channel Knowledge Laboratories Learning Live Birth Maintenance Measurement Mechanics Microelectrodes Modeling Muscle Muscle Cells Muscle Fibers Muscle function Muscular Dystrophies Mutation Myocardium Onset of illness Outcome Pathologic Patients Physicians Physiological Physiological Adaptation Proteins Research Respiratory Failure Scientist Severity of illness Signal Pathway Skeletal Muscle Stress Striated Muscles Study models System Techniques Teenagers Testing Therapeutic Tissues Titrations Training biological adaptation to stress career development clinical phenotype comparison control disease heterogeneity gene network genome-wide human disease improved induced pluripotent stem cell insight male muscle degeneration muscle stress new therapeutic target novel paracrine patch clamp pharmacologic programs recruit response skeletal skeletal muscle differentiation stem transcriptome sequencing

项目摘要

PROJECT SUMMARY Duchenne muscular dystrophy (DMD) is a universally fatal disease. DMD patients do not express dystrophin protein and develop skeletal muscle (SkM) degeneration by age 3-5 with later degeneration in cardiac muscle (CM) by mid-teens. These patients ultimately succumb to respiratory or cardiac failure by age 25-30. The underlying mechanisms that regulate DMD progression are not well understood. Using patient-derived induced pluripotent stem cells (iPSCs) with a spectrum of mutations and disease severity, we can study the mechanisms governing the clinical manifestations of DMD in SkM and CM. Our preliminary data show that DMD patient iPSC- CMs have weaker action potentials and longer field potential duration when compared to control lines. Based on these preliminary results and animal model studies, I hypothesize that loss of dystrophin results in dynamic gene network changes that cause impaired responses to stress stemming from improper development and maintenance of striated muscle’s physiologic functions. I will test this central hypothesis in two specific aims. In Aim 1, I will identify the transcriptional profile and downstream electrophysiological and mechanical adaptations of striated muscle in response to stress in a panel of DMD patient-derived iPSC lines. My working hypothesis is that increasing demand for cell contraction leads to similar compensatory mechanisms in patient-derived iPSC- SkM and -CMs, but the response is more protective in CMs due to their constant recruitment when compared to unaffected controls. Here, I will employ electrical- and pharmacological approaches to induce contractions and analyze the effects via RNA sequencing (bulk and single-cell), electrophysiologic measurements (microelectrode array and whole-cell patch clamp), and membrane permeability assays. Our preliminary studies reveal that, at baseline, DMD iPSC-SkM and -CMs show a leakier plasma membrane when compared to control lines. In Aim 2, I will characterize dose effects of dystrophin on gene networks that regulate the development and maintenance of physiologic muscle function. My working hypothesis is that dystrophin depletion during differentiation of human iPSC-SkM and -CMs results in reversible transcriptional and physiologic changes. Using an inducible and reversible degradation system in unaffected human iPSCs, we can chemically modulate dystrophin protein levels during muscle differentiation and, identify the transcriptional profiles and cellular adaptations in response to varying levels of dystrophin. Collectively, these studies are significant in that they will shed light on transcriptional network changes due to loss of dystrophin in striated muscle that underlie varying clinical phenotype and onset. Further understanding of DMD pathophysiology and its progression may offer new therapeutic targets for muscular dystrophies as well as advance our understanding of normal muscle cell biology and function. The proposed research and training plans provide a rigorous program for successful completion of my MD-PhD degrees and will further my development as an academic physician-scientist.

项目总结

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Dual inhibition of MAPK and PI3K/AKT pathways enhances maturation of human iPSC-derived cardiomyocytes.

DOI：
10.1016/j.stemcr.2022.07.003
发表时间：
2022-09-13
期刊：
STEM CELL REPORTS
影响因子：
5.9
作者：
Garay, Bayardo I.;Givens, Sophie;Abreu, Phablo;Liu, Man;Yucel, Dogacan;Baik, June;Stanis, Noah;Rothermel, Taylor M.;Magli, Alessandro;Abrahante, Juan E.;Goloviznina, Natalya A.;Soliman, Hossam A. N.;Dhoke, Neha R.;Kyba, Michael;Alford, Patrick W.;Dudley Jr, Samuel C.;van Berlo, Jop H.;Ogle, Brenda;Perlingeiro, Rita R. C.
通讯作者：
Perlingeiro, Rita R. C.