SMN缺乏通过诱导自噬持续活化加重缺血再灌注肾损伤的机制研究

编码运动神经元存活蛋白（SMN）基因发生纯合或复合杂合突变导致常染色体隐性遗传脊髓性肌萎缩症，SMN基因杂合缺失（SMN+/-）在人群中的携带频率高达3%。SMN在近端肾小管高表达，本课题组前期发现，SMN+/-小鼠相较野生型小鼠对缺血再灌注肾损伤更易感，同时SMN+/-小鼠IRI后肾小管上皮细胞凋亡加重、细胞自噬持续活化和mTOR激酶活性降低。为进一步探索SMN对IRI的保护作用及分子机制，本项目基于肾小管上皮细胞缺氧再复氧模型和IRI动物模型开展SMN基因敲低和回补实验，研究：1）SMN通过调控细胞自噬影响IRI；2）SMN调控细胞自噬依赖mTOR；3）SMN调控mTOR的分子机制。本项目的开展有望发现急性肾损伤新的防治靶点、有助于阐明急性肾损伤病理生理机制。

Homozygous deletions or mutations of survival of motor neuron (SMN) gene causes spinal muscular atrophy (SMA) and SMN+/- carries, with the prevalence of 3/100 in the population are clinical unaffected throughout their lives. It has been confirmed that SMN was highly expressed in the renal tubular epithelial cells and SMN insufficiency exacerbated I/R-induced kidney injury in heterozygous SMN knockout mice, along with autophagosomes accumulation and mTOR inhibition in the kidney. In this project, SMN knockdown/complementary mouse renal tubule epithelial cells and mice will be used, stimulated by hypoxia/reoxygenation or ischemia-reperfusion, to confirmed the protective mechanism of SMN in the kidney. Thus we hypothesized that knockdown of SMN enhanced autophagy excessive activation via mTOR, which exacerbated I/R-induced kidney injury. The techniques of immunoprecipitation and spectroscopic analysis were used to explore the directly molecules between SMN and mTOR in the process of autophagy activation. The success of this project will provide new insight into physiopathology mechanism of acute kidney injury and rationale for potential therapeutic intervention.