Islet Neogenesis with Ngn3 Therapy Reverses Diabetes

描述（由申请人提供）： 糖尿病的特征是胰岛素相对缺乏。虽然胰岛移植是一种生理性的替代外源性胰岛素的方法，但供体胰岛的短缺和终身免疫抑制的必要性限制了它的应用。诱导内源性胰岛新生将避免这些问题。这已经在糖尿病小鼠中通过将Pdx 1（胰腺分化中的早期转录因子）递送到肝脏来尝试。虽然观察到胰岛素分泌细胞，但由于缺乏胰岛形成和肝脏副作用而受到限制。当使用更下游的转录因子Neurod1时，取得了重大进展。这在逆转糖尿病状态方面是有效的，同时在肝脏中诱导胰岛样簇。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。神经生成素3（Ngn 3）是启动内分泌胰腺分化途径的转录因子，因此是诱导成熟胰岛的极好候选物。正如我们的初步研究所示，Ngn3的异位表达不仅逆转了糖尿病小鼠的高血糖症，而且恢复了正常的葡萄糖耐量。 该提案的目标是确定Ngn 3的异位表达可以逆转糖尿病和恢复葡萄糖耐量，并描绘Ngn 3表达诱导胰岛新生的机制。我们的研究将针对以下具体目标：1）通过递送Ngn 3作为转基因来逆转胰岛素缺乏型糖尿病小鼠中的糖尿病，2）定位和分离诱导的异位胰岛，表征它们的葡萄糖响应性并将它们与正常胰岛进行比较，以及3）确定这些异位胰岛的“起源细胞”并表征胰岛分化程序。 我在乔斯林糖尿病中心和哈佛医学院接受的糖尿病临床和研究培训，沿着我在贝勒医学院担任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糖尿病可行疗法的治疗潜力。Lawrence Chan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，继续我对糖尿病分子治疗学的研究，并进一步发展我的技能，以实现我成为独立研究者的目标。

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.