JMJD3调控TGFB1/SMAD3/IL11通路在间质性膀胱炎/膀胱疼痛综合征（IC/BPS） 膀胱重塑中的作用和机制研究

间质性膀胱炎/膀胱疼痛综合征（IC/BPS）发病率高，严重影响患者生活质量，其患者膀胱壁伴明显纤维化，是导致膀胱功能失常的重要因素，但机制待查。我们前期研究发现：重要表观调控因子JMJD3在IC/BPS患者膀胱组织中高表达；JMJD3促进纤维化基因和炎症因子IL11/IL8表达；重组腺相关病毒（rAAV）rh.10高效安全转导小鼠膀胱组织，且Cas9系统可高效敲除JMJD3。我们计划包装rAAVrh.10-saCas9/sgJMJD3或sgTGFB1或sgIL11病毒，转导膀胱细胞和模型小鼠膀胱组织，分析JMJD3-TGFB1/IL11信号对膀胱细胞增殖，胞外基质累积，膀胱形态功能等的作用，检测JMJD3靶基因表达，结合ATAC测序获得染色质开放图谱，分析JMJD3-TGFB1/IL11信号活性，为阐明JMJD3调控IC/BPS膀胱纤维化发生发展的分子机制及其基因治疗提供重要的依据和基础。

Interstitial cystitis / bladder pain syndrome (IC/BPS) shows high incidence and dramatically decreases the life quality of patients. Bladder wall fibrosis is obviously observed in IC/BPS patients, and it is an important factor that leading to bladder dysfunction, however, the underlying mechanism is unknown. Our previous study found that 1. an important epigenetic regulation factor, JMJD3 showed significantly high expression in bladder tissue of patients with IC/BPS; 2. JMJD3 regulated the expression of fibrosis related genes and IL11/IL8; 3. recombinant adeno-associated virus (rAAV) rh.10 could efficiently and safely transduce mouse bladder tissues, and the Cas9 system can effectively knockout JMJD3 gene. This project proposes to package rAAVrh.10-saCas9/sgJMJD3 or sgTGFB1 or sgIL11 viruses, respectively, to transduce the bladder cells and bladder tissue of IC/BPS mouse model. The effects of JMJD3-TGFB1/IL11 signaling on cell survival, extracellular matrix accumulation, morphology and function of bladder of the IC/BPS model would be analyzed, and the expression of JMJD3 target genes as well as activities of JMJD3-TGFB1/IL11 signaling will be detected using ATAC sequencing. These results could provide important foundation and basis for its underlying molecular mechanism of JMJD3 and gene therapy in the development of IC/BPS associated bladder fibrosis.