利用单细胞测序探索RTN3通过X-IGF2-JAK2调控胶原合成和聚积在肾小球硬化中的作用

慢性肾病（CKD）及其并发症是人类健康的“沉默的杀手”。肾小球硬化是我国CKD的主要类型，但发病机制尚不明确。我们课题组前期发现①RTN3基因敲除小鼠出现明显肾小球硬化；②RTN3基因敲除小鼠肾小球中胶原表达显著增多；③临床部分肾小球硬化患者RTN3表达降低且与胶原含量成反比；④RTN3基因敲除小鼠IGF2和JAK2的表达显著增高；⑤RTN3能与X互作，敲除RTN3能增加X入核。已知X是IGF2的转录激活因子，IGF2-JAK2的增多和激活能促进胶原的合成和聚积，导致肾小球硬化。因此推测：在遗传和/或环境影响下，RTN3表达降低，通过与X的作用调控IGF2-JAK2的表达和激活，促进胶原的合成和聚积，导致肾小球硬化的发生。为证实这一假说，我们拟运用单细胞转录组测序等技术从群体-个体-模式生物-细胞-分子水平，探讨RTN3调控胶原合成和聚积的分子机制，阐明RTN3在肾小球硬化中的作用。

Chronic kidney disease (CKD) and its complications are known as the "silent killers" of human health. Glomerulosclerosis is the major type of CKD in China, but its pathogenic mechanisms are not yet clear. Our group have found: 1) RTN3-KO mice presented obvious glomerulosclerosis; 2) RTN3-KO mice presented significantly increased collagen level in the glomeruli; 3) Patients with glomerulosclerosis have decreased RTN3 expression, the RTN3 level in those patients are inversely proportional to their collagen content; 4) IGF2 and JAK2 in RTN3-KO mice is significantly increased; 5) RTN3 can interact with protein X, while RTN3-KO can increase the entrance of X into the nucleus. Protein X is a transcriptional activator of IGF2. Increased expression and activation of IGF2-JAK2 can promote collagen synthesis and aggregation, leading to glomerular sclerosis. .Therefore, we hypothesized that: under the genetic and/or environmental affection, the expression of RTN3 is reduced, lead to the hyper-activation of X. Then the IGF2-JAK2 pathway are activated due to the increased X, increasing the synthesis and aggregation of collagen, which finally lead to the development of glomerular sclerosis..To confirm this hypothesis, we plan to use single-cell sequencing combined with other technologies to explore the molecular mechanism of RTN3 in regulating collagen synthesis and aggregation from a systematic view, and then clarify the role of RTN3 in glomerulosclerosis.