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

描述(由申请人提供)： Pdx1-VP16和Pax4诱导的胰岛再生逆转糖尿病 已有研究表明，内分泌胰腺具有再生潜能，Exendin-4等多种因子可促进内分泌胰腺再生。内源性β细胞再生的诱导可能会给糖尿病治疗带来革命性变化。尽管如此，到目前为止还没有确定任何强大的再生诱导方案。关键的胰腺转录因子如Pdx1和Pax4已被证明可对干细胞进行重新编程，有利于内分泌胰腺的分化。了解(-细胞再生的因素和机制将指导糖尿病患者增加(-细胞质量)的治疗努力。因此，我们假设在体内将胰腺转录因子(即Pdx1-VP16和Pax4)导入糖尿病小鼠和非人灵长类动物的胰腺将促进胰岛细胞的再生和恢复胰腺的内分泌功能。 在这项研究中，我们将通过以下方法开辟再生之路： 1.研究Pdx1-VP16和Pax4对糖尿病小鼠血糖水平和胰岛细胞再生的影响。 2.研究Pdx1-VP16和Pax4对自发性糖尿病NOD小鼠模型胰岛细胞再生的促进作用。 3.研究AAV8载体将人Pdx1基因导入自发性2型糖尿病(T2 DM)非人类灵长类动物(NHP)胰腺内能否逆转高血糖。 以创新的方式利用胰腺转录因子，以再生因糖尿病失去的胰岛，可能会产生新的治疗策略。

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.