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

项目总结 患有1型糖尿病的患者必须接受负担沉重的、通常是终生的外源性胰岛素 依赖。到目前为止，唯一可用的替代疗法是从身体捐赠者身上移植胰岛。 然而，这种程序带来了障碍，例如现有捐赠者的稀缺和拒绝 通过病人的免疫系统移植细胞。而且，随着时间的推移，移植的胰岛往往会死亡。几个 干细胞的类型，包括胚胎干细胞和诱导多能干细胞，已经被广泛应用。 研究产生葡萄糖反应的胰岛素分泌细胞，代表了一种更可靠的胰岛来源。 然而，移植治疗的一个重要问题是需要免疫抑制药物，这是 表现出长期的副作用，并阻碍了这种方法在大量T1D患者中的可行性。 此外，这些干细胞来源的β细胞的成本效益和大规模生产仍然是主要的 挑战。我们建议应用化学生物学和基因组工程的方法来开发平台 用于对这些β细胞进行高效的分类、生产和编辑。 PHS 398/2590(06/09版)1续订格式页面

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