铁调素调节蛋白在失重性肌萎缩形成中的作用及机制

失重性肌萎缩将严重影响航天员在轨驻留时间和工作绩效，深入认识失重性肌萎缩发生机制，研制有效防治措施，是决定未来长期载人飞行成败的关键。我们首次发现小鼠骨骼肌铁调素调节蛋白（HJV）与TβRII直接结合抑制TGF-β1/Smad3通路的新机制，但HJV是否参与失重性肌萎缩形成及其机制尚不清楚。本研究将采用骨骼肌条件性敲除HJV、比目鱼肌转染pCMV-HJV、pCMV-HJV+shTβRII及其对照小鼠尾悬吊的失重性肌萎缩模型，深入探讨在失重性肌萎缩形成过程中，HJV的动态变化规律及其对慢肌选择性萎缩、慢肌向快肌纤维表型转化的影响；HJV表达水平对失重性肌萎缩关键信号通路TGF-β1/Smad3的影响；并进一步揭示HJV调控失重性肌萎缩TGF-β1/Smad3信号通路的新机制及其调控肌萎缩特异基因和慢肌特异基因转录表达的分子机制。为进一步研发航天肌萎缩的有效防治药物提供潜在药物靶点和候选药物。

Weightlessness muscle atrophy will seriously affect astronauts in orbit dwell time and work performance. How to understand weightlessness muscular atrophy mechanism and develop effective prevention measures is the key to decide success or failure of future long-term manned flight. In previous study, we found the novel mechanism of hemojuvelin (HJV) directly combined with TβRII to regulate TGF-β1/Smad3 signal pathway activation, but whether HJV was involved in weightlessness muscle atrophy keeps unclear. In this study, we will employ skeletal muscle conditional knockout HJV, pCMV-HJV, pCMV-HJV&shTβRII plasmid-transfected mice as well as their controls to develop the models of tail suspension-induced weightlessness muscle atrophy to further investigate that the effects of HJV on the selective atrophy and transition into fast-twitch myofibers of slow-twitch myofibers during muscle atrophy; the influence of HJV expression level on TGF-β1/Smad3 signaling pathway activation; Furthermore, we will reveal the novel mechanism of HJV in regulating TGF-β1/Smad3 signaling pathway and its molecular mechanism which regulates the transcription and expression of muscle atrophy-specific genes and myofiber type-specific gene during muscle atrophy. The study may provide potential drug targets and drug candidates for the development of effective protection and countermeasures for the muscle atrophy during space flight.