Development of platforms for sorting, production, editing of beta cells

项目摘要 患有1型糖尿病的患者必须接受负担沉重的、通常是终身的外源性胰岛素治疗 依赖到目前为止，唯一可用的替代疗法是从尸体供体移植胰岛。 然而，这种程序存在一些障碍，如缺乏可用的捐助者和拒绝接受捐助者。 移植的细胞通过病人的免疫系统。此外，随着时间的推移，移植的胰岛往往会死亡。几 包括胚胎干细胞和诱导多能干细胞在内的干细胞类型已被广泛研究。 研究产生葡萄糖反应的胰岛素分泌细胞，代表了更稳定的胰岛来源。 然而，移植治疗的一个重要问题是需要免疫抑制药物， 表现出长期的副作用，并阻碍了这种方法对大量T1 D患者的可行性。 此外，这些干细胞衍生的β细胞的成本有效和大规模生产仍然是主要的挑战。 挑战.我们建议应用化学生物学和基因组工程方法来开发平台 用于有效地分选、生产和编辑这些β细胞。 PHS 398/2590（Rev. 06/09）1

PROJECT SUMMARY Patients suffering from type 1 diabetes must undergo burdensome, often lifelong, exogenous insulin dependence. Up to now, the only available replacement therapy is to transplant islets from cadaveric donors. However, such procedures present hurdles such as the scarcity of available donors and the rejection of transplanted cells by the patient’s immune system. Also, over time, the transplanted islets tend to die. Several types of stem cells, including embryonic stem cell and induced pluripotent stem cell, have been extensively studied to generate glucose-responsive insulin-secreting cells and represents a more tenable source of islets. However, a significant concern for transplantation therapy is the need for immunosuppressive drugs, which exhibit long term side effects and hinders the feasibility of this approach to the large population of T1D patients. Furthermore, cost-effective and large-scale production of these stem cell-derived beta cells is still a major challenge. We propose to apply chemical biology and genome engineering approaches to develop platforms for efficient sorting, production, and editing of these beta cells. PHS 398/2590 (Rev. 06/09) 1 Continuation Format Page