Novel Strategies to Increase Insulin Independence after Islet Autotransplantation

胰岛自体移植后提高胰岛素独立性的新策略

• 批准号: 8728231
• 负责人: Hongjun Wang
• 金额: $ 7.25万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8728231
• 关键词: Allogenic; Allografting; Animals; Apoptosis; Autologous Transplantation; Beta Cell; Biomedical Engineering; Brittle diabetes; Carbon Monoxide; Cell Death; Cell Survival; Cell physiology; Cells; Cyclic GMP; Data; Diabetes Mellitus; Encapsulated; Endocrinologist; Funding; Gene Expression; Genes; Glycolates; Goals; Harvest; Homologous Transplantation; Human; Hypoxia; Immune; Individual; Inflammation; Inflammatory; Infusion procedures; Injury; Insulin; Insulin-Dependent Diabetes Mellitus; Intractable Pain; Islet Cell; Islets of Langerhans Transplantation; Lead; Learning; Liver; Medical; Modeling; Mus; NOD/SCID mouse; Nutrient; Operative Surgical Procedures; Pancreas; Patients; Postoperative Period; Procedures; Protocols documentation; Quality of life; Reactive Oxygen Species; Research; Resistance; Rest; South Carolina; Streptozocin; Surgeon; Testing; Total Pancreatectomy; Translating; Translations; Transplant Recipients; Transplantation; United States; Universities; base; bench to bedside; chronic pancreatitis; cytokine; deprivation; diabetic; heme oxygenase-1; implantation; improved; in vivo; islet; islet allograft; nanoparticle; novel; novel strategies; nutrition; prevent; response; stressor; treatment strategy

DESCRIPTION (provided by applicant): Total pancreatectomy with islet autotransplantation (TP-IAT) is currently being performed to treat intractable pain and to prevent "brittle" diabetes in well-selected patients with chronic pancreatitis. A major problem associated with TP-IAT is that the number of islets available for transplantation is compromised by a severely diseased and fibrotic pancreas. Moreover, as many as 50-60% of islet cells undergo apoptosis immediately after intraportal infusion when transplantation-associated stressors (hypoxia, nutrient deprivation, reactive oxygen species, proinflammation cytokines, etc.) are induced during harvesting, isolation, and implantation of the islet cell mass. Although the quality of life are significantly improved in our TP-IAT patients, ony 25% of them become insulin independent (compared to >85% pre-operatively), 19% require minimal insulin (<10u/day) replacement and the rest develop pancreatogenic diabetes after surgery. Strategies that produce islets more "robust" to resist stressors that induce ¿ cell apoptosis are extremely appealing to prevent onset of surgical diabetes and to improve the efficiency of human islet auto-transplantation. We have been focused on exploring strategies that can prevent islet ¿ cell death after allogeneic transplantation to treat patient with type 1 diabetes over the past 10 years. Our data indicate that induction of a protective gene, heme oxygenase-1 (HO-1), or exposing the product of HO-1 enzymatic activity, carbon monoxide (CO), protects islet allografts from immune rejection after transplantation. HO-1 gene expression was dramatically reduced in islets from chronic pancreatitis patient compared to those from healthy individual and HO-1 induction protects islets from hypoxia-induced cell death. Moreover, encapsulating islets with biodegradable poly-lactic-co-glycolic acid (PLGA) nanoparticles also protect islets from apoptosis in a murine islet transplantation model. We hypothesize that induction of HO-1/CO exposure, in combination with islet encapsulation, can make human islets more resistant to injuries and lead to better survival after transplantation so that more patients with chronic pancreatitis can be diabetes free after TP-IAT. In this proposal, we aim to develop a novel HO-1/CO-based islet encapsulation protocol that can make islets more resistant to injuries encountered during isolation and after transplantation so that more patients with chronic pancreatitis can be diabetes free after TP-IAT. Our strong research team that includes islet transplantation biologists, islet transplantation surgeons, endocrinologists and bioengineering experts, and our state-of-the-art cGMP facility at MUSC offers a convenient and powerful platform that can facilitate the translation of our research findings from bench to bedside.

描述（由申请人提供）： 目前正在对精心挑选的慢性胰腺炎患者进行全胰腺切除术联合胰岛自体移植（TP-IAT），以治疗顽固性疼痛并预防“脆性”糖尿病。严重病变和纤维化的胰腺会损害移植，此外，当与移植相关时，在门静脉内输注后，多达 50-60% 的胰岛细胞立即发生凋亡。尽管我们的 TP-IAT 患者的生活质量显着改善，但在胰岛细胞团的采集、分离和植入过程中会引发应激源（缺氧、营养缺乏、活性氧、促炎细胞因子等）。其中的患者变得不依赖胰岛素​​（与术前 >85% 相比），19% 需要最少的胰岛素（<10u/天）替代，其余的则在手术后发展为胰源性糖尿病。产生更“稳健”的胰岛以抵抗诱发 ¿细胞凋亡对于预防手术糖尿病的发生和提高人类胰岛自体移植的效率非常有吸引力，我们一直致力于探索可以预防胰岛的策略。过去 10 年来，同种异体移植治疗 1 型糖尿病患者后细胞死亡，我们的数据表明，诱导了保护性基因血红素加氧酶-1 (HO-1)，或暴露了 HO-1 酶活性的产物碳。一氧化物 (CO)，可保护胰岛同种异体移植物免受移植后的免疫排斥，与健康个体和 HO-1 诱导相比，慢性胰腺炎患者的胰岛中的 HO-1 基因表达显着降低。此外，在小鼠胰岛移植模型中，用可生物降解的聚乳酸-乙醇酸 (PLGA) 纳米粒子封装胰岛也可以保护胰岛免于细胞凋亡。与胰岛封装相结合，可以使人类胰岛具有更强的抗损伤能力，并在移植后获得更好的生存率，使更多的慢性胰腺炎患者在移植后能够摆脱糖尿病。在本提案中，我们的目标是开发一种新型的基于 HO-1/CO 的胰岛封装方案，使胰岛对隔离期间和移植后遇到的损伤具有更强的抵抗力，从而使更多的慢性胰腺炎患者在术后能够摆脱糖尿病。 TP-IAT。我们强大的研究团队包括胰岛移植生物学家、胰岛移植外科医生、内分泌学家和生物工程专家，以及我们位于 MUSC 的最先进的 cGMP 设施，为您提供了便利强大的平台可以促进我们的研究成果从实验室到临床的转化。