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

Pdx1-VP16 和 Pax4 诱导的胰岛再生逆转糖尿病

• 批准号: 8277060
• 负责人: DONGQI DQ TANG
• 金额: $ 0.26万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-06-01 至 2012-08-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8277060
• 关键词: Autoimmunity; Beta Cell; Blood Glucose; C-Peptide; Cell physiology; Cells; Diabetes Mellitus; Diabetic mouse; Endocrine; Gene Expression Profile; Gene Family; Glucose tolerance test; Human; Hyperglycemia; Inbred NOD Mice; Injection of therapeutic agent; Insulin; Intraperitoneal Injections; Islet Cell; Islets of Langerhans; Mus; Natural regeneration; Non-Insulin-Dependent Diabetes Mellitus; Pancreas; Patients; Performance; Process; Protocols documentation; Serum; Stem cells; Streptozocin; Therapeutic; Total Pancreatectomy; VP 16; adeno-associated viral vector; diabetes mellitus therapy; diabetic; exenatide; in vivo; innovation; intraperitoneal; islet; mouse model; nonhuman primate; novel therapeutics; pancreas development; transcription factor; vector

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 n fi-cell regeneration will guide therapeutic efforts to augment fi-cell mass in patients with diabetes. Therefore, we hypothesize that in vivo delivery of pancreatic transcription factors (i.e., Pdx1-VP16 and Pax4) nto the pancreas of diabetic mice and nonhuman primates will promote islet cell regeneration and restore oancreatic 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.

Pdx1-VP16和Pax4诱导的胰岛再生逆转糖尿病 已经证明，内分泌胰腺具有再生的潜力，这一过程可能 受Exendin-4等多种因素的推动。内源性β细胞再生的诱导可以 彻底改变糖尿病的治疗方法。尽管如此，还没有确定可靠的再生诱导方案 到目前为止。关键的胰腺转录因子如Pdx1和Pax4已被证实可重新编程 干细胞有利于胰腺内分泌分化。了解所涉及的因素和机制 NFI细胞再生将指导糖尿病患者增加FI细胞质量的治疗努力。 因此，我们假设在体内传递胰腺转录因子(即Pdx1-VP16和Pax4) 糖尿病小鼠和非人灵长类动物的胰腺移植将促进胰岛细胞的再生和恢复 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之路： 1.检测Pdx1-VP16和Pax4载体对小鼠血糖和胰岛细胞的影响 糖尿病小鼠模型的再生。 2.检测Pdx1-VP16和Pax4对小鼠胰岛细胞再生的影响。 在自身免疫控制和不控制自身免疫的环境中建立自发糖尿病NOD小鼠模型。 3.研究AAV8载体能否将人Pdx1基因导入非人灵长类动物的胰腺 自发性T2 DM患者(NHP)可逆转高血糖。 利用胰腺转录因子可能会产生新的治疗策略 创新的方法，以再生因糖尿病失去的胰岛。