Islet Neogenesis with Ngn3 Therapy Reverses Diabetes

描述(由申请人提供)： 糖尿病的特征是相对缺乏胰岛素。虽然胰岛移植是外源性胰岛素的一种生理替代方法，但供体胰岛短缺和终生免疫抑制的必要性限制了其应用。诱导内源性胰岛新生可以绕过这些问题。在糖尿病小鼠中，已经尝试过将Pdx1--一种胰腺分化的早期转录因子--输送到肝脏。虽然可以看到胰岛素分泌细胞，但这受到胰岛形成不足和肝脏副作用的限制。当使用一种更下游的转录因子Neurod1时，取得了显著的进步。这在逆转糖尿病状态的同时在肝脏中诱导胰岛样簇是有效的。然而，由于这些簇是不成熟的，仍然需要更好的策略来诱导胰岛新生。神经原蛋白3(Neurogenin3，Ngn3)是启动内分泌胰腺分化途径的转录因子，是诱导成熟胰岛的极佳候选基因。我们的初步研究表明，异位表达Ngn3不仅可以逆转糖尿病小鼠的高血糖，还可以恢复正常的糖耐量。 这项建议的目的是建立异位表达Ngn3可以逆转糖尿病和恢复糖耐量，并描述Ngn3表达诱导胰岛新生的机制。我们的研究将针对以下特定目标：1)通过转基因Ngn3逆转胰岛素缺乏糖尿病小鼠的糖尿病；2)定位和分离诱导的异位胰岛，表征其葡萄糖反应性，并将其与正常胰岛进行比较；3)确定这些异位胰岛的“细胞来源”，并表征胰岛的分化程序。 我在Joslin糖尿病中心和哈佛医学院接受的糖尿病临床和研究培训，以及我在贝勒医学院分子医学研究员的研究经验，为我提供了一个独特的视角来探索胰岛新生作为一种可行的糖尿病疗法的治疗潜力。劳伦斯·陈教授的指导支持和贝勒医学院的学术环境为我提供了一个极好的机会来继续我对糖尿病分子疗法的研究，并进一步发展我的技能，以实现我成为一名独立研究员的目标。

DESCRIPTION (provided by applicant): Diabetes is characterized by a relative deficiency of insulin. Though islet transplantation is a physiological alternative to exogenous insulin, donor islet shortage and the necessity of lifetime immunosupression limit its application. Inducing endogenous islet neogenesis would circumvent these problems. This has been attempted in diabetic mice by delivering Pdx1, an early transcription factor in pancreatic differentiation, to the liver. Though insulin secreting cells were seen, this was limited by lack of islet formation and hepatic side effects. A significant advance was made when Neurod1, a more down-stream transcription factor, was used. This was effective in reversing the diabetic state while inducing islet-like clusters in the liver. However, as these clusters were immature, there remains a need for better strategies to induce islet neogenesis. Neurogenin3 (Ngn3) is the transcription factor that initiates the differentiation pathway of the endocrine pancreas and thus is an excellent candidate for inducing mature islets. As shown by our preliminary studies, ectopic expression of Ngn3 not only reverses hyperglycemia in diabetic mice but also restores normal glucose tolerance. The goals of this proposal are to establish that ectopic expression of Ngn3 can reverse diabetes and restore glucose tolerance and to delineate the mechanisms by which Ngn3 expression induces islet neogenesis. Our studies will be directed at the following specific aims: 1) to reverse diabetes in insulin deficient diabetic mice by delivering Ngn3 as a transgene, 2) to localize and isolate the induced ectopic islets, characterize their glucose responsiveness and compare them with normal pancreatic islets and 3) to determine the 'cell-of-origin' of these ectopic islets and characterize the islet differentiation program. My clinical & research training in Diabetes at Joslin Diabetes Center and Harvard Medical School, along with my research experience as a fellow in Molecular Medicine at Baylor College of Medicine provide me with a unique perspective to explore the therapeutic potential of islet neogenesis as a viable therapy for diabetes. The mentoring support of Professor Lawrence Chan and the academic environment of Baylor College of Medicine provide me with an excellent opportunity to continue my investigation into molecular therapeutics of diabetes and further develop my skills to attain my goal of being an independent investigator.