骨髓间充质干细胞（BMSCs）自我更新潜能减弱是糖尿病骨修复能力减弱的重要原因，但具体机制不清。我们前期发现Lhx8是促进BMSCs自我更新的关键基因。进一步研究发现，糖尿病条件下的BMSCs中，Lhx8表达降低与该基因附近长链非编码RNA（lncRNA） AI606473表达增加有关，表达增加的AI606473可能通过DNA甲基转移酶DNMT1诱导Lhx8启动子区甲基化和表达抑制，是糖尿病BMSCs自我更新能力降低的潜在机制。本项目拟结合前期研究基础，首先通过干预AI606473表达观察糖尿病BMSCs自我更新能力变化，明确该lncRNA的生物学功能，然后通过分子生物学方法揭示AI606473调控Lhx8表达的表观遗传学机制，最后结合光遗传学技术探讨时空特异性干预AI606473策略对提升糖尿病BMSCs骨再生能力的可行性。本项目有望发现糖尿病骨修复能力减弱的新机制，为其防治提供新策略。

The diminished self-renewal potential of bone marrow mesenchymal stem cells (BMSCs) is one of the important reasons for the reduction of bone regeneration under diabetes states. However, its mechanism remains unclear. The applicants revealed that homeobox gene Lhx8 was the key gene to promote self-renewal of MSCs. Further, we found that down-regulated expression of Lhx8 was associated with up-regulated expression of long non-coding RNA (lncRNA) AI606473 under diabetes states. The mechanism, in which overexpressed AI606473 may suppress Lhx8 expression by recruiting DNA methyltransferase 1 (DNMT1) to the promoter motif of Lhx8, offers a potential explanation to the weakened self-renewal of MSCs under diabetes states. In light of the previous research, this program aims to clarify the biological functions of AI606473 through observing changes after intervening the its expression. Afterwards, using molecular biology methods to reveal the epigenetic mechanism in which AI606473 regulating Lhx8 expression. Last, together with optogenetic tools, determining the feasibility that improves bone regeneration under diabetes states through intervening the AI606473 expression spatiotemporally. This program holds promise of discovering a new mechanism that weakens bone regeneration under diabetes states and may provide new strategies for its prevention and treatment.