Modulating the senescence secretome to block progression of T1D

1型糖尿病是一种器官特异性自身免疫性疾病，其特征在于由于胰腺β细胞的进行性损失而导致的高血糖症。我们已经发现，在T1D期间，小鼠和人的胰腺β细胞获得了衰老相关分泌表型（SASP）的命运。衰老的β细胞可以通过促进旁观者衰老和免疫监视以旁分泌方式重塑胰岛环境。我们已经开发出选择性消除SASP β细胞的药物，而不改变参与疾病的主要免疫细胞类型的丰度。值得注意的是，SASP β细胞的消除阻止了β细胞破坏的进展，足以预防糖尿病（Thompson等人，2019 Cell Metabolism in press）。在这项提案中，我们解决了DNA损伤如何导致β细胞在T1D环境中获得衰老的命运以及DNA修复过程在诱导DNA损伤中的作用。这种理解对于确定我们如何指导DNA修复途径以消除或抑制β细胞的衰老至关重要。我们还研究了衰老β细胞的转录和染色质变化，以及我们是否可以靶向关键调控因子来抑制衰老表型。最后，我们探讨了衰老β细胞的细胞外囊泡是否参与细胞间通讯和传递信号以调节免疫反应。这种方法将拓宽我们对T1D中β细胞衰老的新发现，并为治疗开发提供新的方向。

Type 1 Diabetes is an organ-specific autoimmune disease characterized by hyperglycemia due to progressive loss of pancreatic beta cells. We have discovered that during T1D, pancreatic beta cells in mice and human acquire a fate reminiscent of senescence associated secretory phenotype (SASP). Senescent beta cells can remodel the islet environment in a paracrine manner by promoting bystander senescence and immune surveillance. We have developed drugs that selectively eliminated SASP beta cells without altering the abundance of the major immune cell types involved in the disease. Significantly, elimination of SASP beta cells halted progression of beta cell destruction and was sufficient to prevent diabetes (Thompson et al, 2019 Cell Metabolism in press). In this proposal, we address how DNA damage leads beta cells to acquire a senescent fate in a T1D setting and the role of DNA repair processes in inducing DNA damage. Such understanding will be important to establish how we can direct DNA repair pathways to eliminate or dampen the senescence of beta cells. We also investigate the transcriptional and chromatin changes in senescent beta cells and whether we can target key regulators to dampen the senescence phenotype. Finally, we explore whether extracellular vesicles from senescent beta cells are involved in cell-cell communication and transmitting signals to regulate the immune response. Such an approach will broaden upon our new finding on beta cell senescence in T1D and provide new direction to therapeutic development.