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Opto-Electrophysiological Method to Study Human Skeletal Muscle Channelopathies

Opto-Electrophysiological Method to Study Human Skeletal Muscle Channelopathies
研究人类骨骼肌通道病的光电生理学方法
批准号:
10596561
负责人:
Marino Di Franco
金额:
$15.44万
依托单位国家:
美国
项目类别:
财政年份:
2022
资助国家:
美国
项目状态:
未结题
起止时间:
2022-04-01 至 2025-01-31

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英文摘要
ABSTRACT Myopathies stemming from mutations in genes coding for ion channels or proteins that regulate their pre-RNA splicing are called, respectively, channelopathies and spliceopathies. Abnormal expression, structure or function of ion channels resulting from those mutations leads to altered muscle electrophysiology and excitation- contraction coupling. These genetic disorders have currently no cure, severely affect the quality of life of patients and span the prevalence spectrum from rare diseases (e.g. hypo- and hyperkalemic periodic paralysis, 1:100000) to the most common myopathies (e.g. dystrophic myotonia, 1-5:10000). While their genetic cause is readily identifiable, understanding the mechanisms underlying channelopathies and spliceopathies, and designing sound therapeutic strategies for them, demands detailed electrophysiological studies performed in the all- meaningful human cellular context. These studies, though feasible, are impeded by a pervasive lack of practical, high throughput methods amenable for use in human muscles. Animal models used to circumvent this shortcoming often fail to recapitulate most diseases or to reproduce the human response to therapeutic drugs. We intend to overcome these limitations by designing and testing a novel, practical electrophysiological method facilely used with human muscle fibers dissected from biopsies. We will combine a revolutionary experimental chamber with technologies from two different electrophysiological methods to perform quantitative, state of the art, electrophysiological studies in segments of fibers 50-400μm long in near-ideal conditions. Unlike previous methods, this new method is readily implemented, user-friendly, and affords the requisite high throughput for statistically significant studies. Our method will allow case-by-case electrophysiological studies and screening of acutely acting drugs, enabling the design of patient specific treatment schemes, coinciding with current trends in contemporary precision medicine. We expect, then, our method will have a transformative impact in human muscle physiology and pathophysiology.
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Opto-Electrophysiological Method to Study Human Skeletal Muscle Channelopathies
Optogenetic control of skeletal muscle excitability
Optogenetic control of skeletal muscle excitability
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