Targeting Senescence for Biomarkers and Therapeutics

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。虽然在理解免疫介导的β细胞破坏方面取得了重大进展，但β细胞功能障碍在T1D潜在病因中的作用尚不清楚。我们已经发现，胰腺β细胞获得促炎分泌组，让人想起在小鼠和人类T1D期间的SASP。SASP 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。在这项提案中，我们专注于人类β细胞，并表征SASP对胰岛微环境的非细胞自主作用，并开发可选择性靶向人类SASP β细胞的药物。我们利用SASP β细胞的分泌特性来鉴定可以报告药物治疗效果和疾病进展的生物标志物。

Type 1 Diabetes is an organ-specific autoimmune disease characterized by hyperglycemia due to progressive loss of pancreatic beta cells. While there has been significant progress in understanding immune-mediated beta cell destruction, the role of beta cell dysfunction in the underlying etiology of T1D is less clear. We have discovered that pancreatic beta cells acquire a proinflammatory secretome reminiscent of SASP during T1D in mice and human. SASP 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. In this proposal, we focus on human beta cells and characterize the non-cell autonomous effects of SASP on islet microenvironment and develop drugs that can selectively target human SASP beta cells. We utilize the secretory properties of SASP beta cells to identify biomarkers that can report on the efficacy of drug treatment and progression of the disease.