Sox9对I型糖尿病胰岛β细胞命运的影响及对胰岛内免疫微环境的调控机制的研究

Type 1 diabetes (T1D)is a multi-stage autoimmune disorder characterized by hyperglycemia that results from specific islet β-cell destruction and loss of insulin secretion. Although exogenous insulin can compensate for insulin deficiency to control blood sugar and alleviate chronic diabetes complications, it cannot restore theβ-cell destruction through intervening the immune microenviroment of pancreas islet. Sry (sex determining region Y)-box 9 (Sox9), as a highly conserved family of transcription factors, plays crucial and diverse roles during development of various organs, including testis, pancreas, intestine, brain, kidney and heart. During the development of pancreas, almost all the pancreas cells are derived from Sox9+ pancreatic progenitor cells. After birth, almost all the pancreas β-cells are derived from preexisting pancreas β-cells. In our previous study, we found that the pancreas β-cells can express increased Sox9 in the development of T1D. In this study, we aim to investigate the fate tracing of islet beta cells in the development of T1D by using the tracing in vivo, to determine whether the remaining pancreatic islet cells can proliferate and form a new cell. The effect of Sox9 on the T1D process and the regulation of the immune microenvironment in the islet were studied by constructing the specific Sox9 gene knockout mice.

I型糖尿病(Type 1 diabetes，T1D)是由自身免疫反应介导的胰岛β细胞损伤导致胰岛素合成不足而引起的高糖血症。虽然外源性胰岛素的使用可以弥补体内胰岛素不足而有效地控制血糖和减弱慢性糖尿病并发症，但胰岛素并不能彻底改变胰岛的免疫微环境并减弱自身免疫反应对胰岛β细胞的损伤。Sox9是一种较为保守的转录因子，在多种器官的发育过程中起着重要作用，包括睾丸、胰腺、肠道、大脑、肾脏和心脏。在胰腺的发育过程中，胰腺中几乎所有的细胞都来自表达Sox9的胰腺祖细胞，而在出生后，胰岛β细胞均来自现存的胰岛β细胞。前期研究发现，Sox9在I型糖尿病鼠的胰岛β细胞中明显表达。本项目拟通过体内示踪技术研究胰岛β细胞在T1D发展过程中的命运轨迹，明确残存的胰岛β细胞是否能增殖形成新生β细胞，通过构建β细胞特异性Sox9功能活性缺失鼠进一步探索Sox9对T1D进程的影响及其对胰岛内免疫微环境的调节作用。

自身免疫反应引起的胰腺β细胞损伤导致胰岛素分泌减少是1型糖尿病(T1DM)的病理基础。因此，寻求减轻胰腺β细胞损伤的新分子靶点，将为T1DM的防治提供实验依据。SRY-box 9 (Sox9)不仅是调控各器官发育的重要分子，其高表达还会加重各种疾病的病理过程。此外，Sox9+细胞也是胰腺祖细胞，参与损伤引起的胰腺修复反应。在我们的研究中，链脲佐菌素(STZ)诱导的胰腺β细胞损伤后，血糖升高和胰腺β细胞缺乏随着时间的推移几乎恢复正常，这意味着STZ诱导的胰腺β细胞损伤后再生。特别是，在胰腺β细胞再生过程中，Sox9的表达明显升高。在此基础上，我们进行了体外实验，验证过表达Sox9是否能抑制炎症因子对胰腺β细胞的损伤。我们的结果表明，过表达Sox9可以减轻炎症因子对胰腺β细胞的损伤，改善炎症因子对胰腺β细胞胰岛素分泌的抑制作用。而且，用STZ处理胰腺β细胞特异性敲除的Sox9小鼠后，血糖水平、胰岛素含量和胰腺β细胞数量未能及时恢复到接近正常水平，进一步证实了Sox9在促进胰腺β细胞修复或再生中的重要性。我们的研究表明，增强的Sox9活性可能保护胰腺β细胞免受自身免疫诱导的损伤，从而改善T1DM的病理过程。