Reveresal of Diabetes by Pdx1-VP16 and Pax4-Induced Islet Regeneration

描述（由申请人提供）： Pdx 1-VP 16和Pax 4诱导胰岛再生对糖尿病的治疗作用 已经证明内分泌胰腺具有再生潜力，并且该过程可以通过许多因素如Exendin-4来促进。内源性β细胞再生的诱导可以彻底改变糖尿病治疗。然而，迄今为止还没有确定稳健的再生诱导方案。胰腺关键转录因子如Pdx 1和Pax 4已被证明可重编程干细胞，有利于胰腺内分泌分化。了解β-细胞再生的因素和机制将指导治疗努力，以增加糖尿病患者的β-细胞质量。因此，我们假设胰腺转录因子的体内递送（即，Pdx 1-VP 16和Pax 4）进入糖尿病小鼠和非人灵长类动物的胰腺中将促进胰岛细胞再生并恢复胰腺内分泌功能。 在这项研究中，我们将通过以下方法开辟再生途径： 1.确定Pdx 1-VP 16和Pax 4递送对糖尿病小鼠模型中血糖水平和胰岛细胞再生的影响。 2.确定Pdx 1-VP 16和Pax 4在有和没有自身免疫控制的情况下对自发性糖尿病NOD小鼠模型中促进胰岛细胞再生的作用。 3.研究通过AAV 8载体将人Pdx 1递送至患有自发性T2 DM的非人灵长类动物（NHP）的胰腺是否可以逆转高血糖症。 新的治疗策略可能会产生于以创新的方式利用胰腺转录因子，以再生因糖尿病而失去的胰岛。

DESCRIPTION (provided by applicant): Reversal of Diabetes by Pdx1-VP16 and Pax4 Induced Islet Regeneration It has been demonstrated that endocrine pancreas has a potential to regeneration and the process could be facilitated by many factors like Exendin-4. The induction of endogenous beta cell regeneration could revolutionize diabetes therapy. Nonetheless, no robust regeneration-inducing protocol has been determined so far. Key pancreatic transcription factors such as Pdx1 and Pax4 has been demonstrated to reprogram stem cell in favor of endocrine pancreas differentiation. Understanding the factors and mechanisms involved in (-cell regeneration will guide therapeutic efforts to augment (-cell mass in patients with diabetes. Therefore, we hypothesize that in vivo delivery of pancreatic transcription factors (i.e., Pdx1-VP16 and Pax4) into the pancreas of diabetic mice and nonhuman primates will promote islet cell regeneration and restore pancreatic endocrine function. In this study, we will blaze the trail to regeneration through the following approach: 1. To determine the effect of Pdx1-VP16 and Pax4 delivery on blood glucose levels and islet cell regeneration in a diabetic mouse model. 2. To determine the effects of Pdx1-VP16 and Pax4 on promoting islet cell regeneration in a spontaneous diabetic NOD mouse model in settings with and without control of autoimmunity. 3. To examine whether delivery of human Pdx1 by AAV8 vector to the pancreas of non-human primates (NHP) suffering from spontaneous T2DM can reverse hyperglycemia. It is possible that new therapeutic strategies may arise from harnessing pancreatic transcription factors in innovative ways in order to regenerate islets lost to diabetes.