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: 8583370
• 负责人: Hongjun Wang
• 金额: $ 7.48万
• 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 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8583370
• 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)： 全胰腺切除加自体胰岛移植(TP-IAT)目前正被用于治疗顽固性疼痛和预防慢性胰腺炎患者的“脆性”糖尿病。与TP-IAT相关的一个主要问题是，可供移植的胰岛数量受到严重病变和纤维化的胰腺的影响。此外，多达50%-60%的胰岛细胞在门脉内输注后，当移植相关应激因素(缺氧、营养剥夺、活性氧、促炎细胞因子等)时立即发生凋亡。在胰岛细胞团的收获、分离和植入过程中被诱导。尽管我们的TP-IAT患者的生活质量得到了显著改善，但只有25%的患者实现了胰岛素非依赖性(与术前85%的患者相比)，19%的患者需要最低限度的胰岛素替代(&lt；10U/天)，其余的患者在手术后发展为胰源性糖尿病。对于预防外科糖尿病的发病和提高人类胰岛自体移植的效率来说，产生更“健壮”的胰岛以抵抗诱导细胞凋亡的应激源是非常有吸引力的。在过去的10年里，我们一直致力于探索预防同种异体移植治疗1型糖尿病患者后胰岛细胞死亡的策略。我们的数据表明，诱导保护性基因血红素加氧酶-1(HO-1)，或暴露HO-1酶活性的产物一氧化碳(CO)，可以保护同种异体胰岛移植物免受移植后的免疫排斥。与健康人相比，慢性胰腺炎患者胰岛HO-1基因表达显著降低，HO-1诱导保护胰岛免受缺氧诱导的细胞死亡。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)纳米颗粒包裹胰岛也可以保护胰岛免受细胞凋亡的影响。我们推测，诱导HO-1/CO暴露，结合胰岛包膜，可以使人胰岛对损伤更具抵抗力，并导致移植后更好的存活，从而使更多的慢性胰腺炎患者在TP-IAT后可以无糖尿病。在这个方案中，我们的目标是开发一种新的基于HO-1/CO的胰岛包埋方案，使胰岛对分离过程中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TP-IAT后可以无糖尿病。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，以及我们在南加州大学最先进的cGMP设施，提供了一个方便而强大的平台，可以促进我们的研究成果从工作台到床边的转换。