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

基本信息

  • 批准号:
    8728231
  • 负责人:
  • 金额:
    $ 7.25万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 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

项目摘要

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。与 TP-IAT 相关的一个主要问题是可用于移植的胰岛数量受到严重患病和纤维化的胰腺的影响。此外,当在胰岛细胞团的收获、分离和植入过程中诱导移植相关的应激源(缺氧、营养缺乏、活性氧、促炎细胞因子等)时,多达50-60%的胰岛细胞在门静脉内输注后立即发生凋亡。尽管我们的 TP-IAT 患者的生活质量显着改善,但其中只有 25% 的患者变得不依赖胰岛素​​(与术前 >85% 相比),19% 的患者需要最少的胰岛素(<10u/天)替代,其余的患者在手术后发展为胰源性糖尿病。产生更“稳健”的胰岛以抵抗诱导细胞凋亡的应激源的策略对于预防手术糖尿病的发作和提高人类胰岛自体移植的效率非常有吸引力。过去 10 年来,我们一直致力于探索可预防异体移植治疗 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 酶活性产物一氧化碳 (CO),可以保护同种异体胰岛移植物在移植后免受免疫排斥。与健康个体相比,慢性胰腺炎患者的胰岛中 HO-1 基因表达显着降低,HO-1 诱导可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)纳米粒子封装胰岛也可以保护胰岛免于凋亡。我们假设诱导 HO-1/CO 暴露与胰岛封装相结合,可以使人类胰岛更能抵抗损伤,并在移植后获得更好的存活率,从而使更多慢性胰腺炎患者在 TP-IAT 后可以摆脱糖尿病。在本提案中,我们的目标是开发一种基于 HO-1/CO 的新型胰岛封装方案,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,从而使更多慢性胰腺炎患者在 TP-IAT 后能够摆脱糖尿病。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,以及我们位于 MUSC 的最先进的 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实验室到临床的转化。

项目成果

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Hongjun Wang其他文献

Hongjun Wang的其他文献

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{{ truncateString('Hongjun Wang', 18)}}的其他基金

Safety and Efficacy of Mesenchymal Stem Cells in the Treatment of Chronic Pancreatitis and Its Associated Pain
间充质干细胞治疗慢性胰腺炎及其相关疼痛的安全性和有效性
  • 批准号:
    10721284
  • 财政年份:
    2023
  • 资助金额:
    $ 7.25万
  • 项目类别:
Autologous BM-MSCs and Islet Co-transplantation to Enhance Islet Survival and Function in TP-IAT Patients
自体 BM-MSC 和胰岛联合移植可增强 TP-IAT 患者的胰岛存活和功能
  • 批准号:
    10474572
  • 财政年份:
    2021
  • 资助金额:
    $ 7.25万
  • 项目类别:
Autologous BM-MSCs and Islet Co-transplantation to Enhance Islet Survival and Function in TP-IAT Patients
自体 BM-MSC 和胰岛联合移植可增强 TP-IAT 患者的胰岛存活和功能
  • 批准号:
    10315988
  • 财政年份:
    2021
  • 资助金额:
    $ 7.25万
  • 项目类别:
Autologous BM-MSCs and Islet Co-transplantation to Enhance Islet Survival and Function in TP-IAT Patients
自体 BM-MSC 和胰岛联合移植可增强 TP-IAT 患者的胰岛存活和功能
  • 批准号:
    10640946
  • 财政年份:
    2021
  • 资助金额:
    $ 7.25万
  • 项目类别:
hAAT-engineered Mesenchymal Stem Cells for the Treatment of Chronic Pain
hAAT 工程改造的间充质干细胞用于治疗慢性疼痛
  • 批准号:
    10292900
  • 财政年份:
    2019
  • 资助金额:
    $ 7.25万
  • 项目类别:
hAAT-engineered Mesenchymal Stem Cells for the Treatment of Chronic Pain
hAAT 工程改造的间充质干细胞用于治疗慢性疼痛
  • 批准号:
    10044402
  • 财政年份:
    2019
  • 资助金额:
    $ 7.25万
  • 项目类别:
hAAT-engineered Mesenchymal Stem Cells for the Treatment of Chronic Pain
hAAT 工程改造的间充质干细胞用于治疗慢性疼痛
  • 批准号:
    10515305
  • 财政年份:
    2019
  • 资助金额:
    $ 7.25万
  • 项目类别:
Cellular Therapy for Type 1 Diabetes using Mesenchymal Stem Cells
使用间充质干细胞进行 1 型糖尿病的细胞疗法
  • 批准号:
    10599910
  • 财政年份:
    2019
  • 资助金额:
    $ 7.25万
  • 项目类别:
Cellular Therapy for Type 1 Diabetes using Mesenchymal Stem Cells
使用间充质干细胞进行 1 型糖尿病的细胞疗法
  • 批准号:
    10376342
  • 财政年份:
    2019
  • 资助金额:
    $ 7.25万
  • 项目类别:
Micro- and nanofiber enabled biomimetic periosteum for bone repair and reconstruction
微米和纳米纤维仿生骨膜用于骨修复和重建
  • 批准号:
    9026932
  • 财政年份:
    2016
  • 资助金额:
    $ 7.25万
  • 项目类别:

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Establishment of novel osteochondral allografting combined with growth factor- collagen-binding domain fusion technology
新型同种异体骨软骨移植联合生长因子-胶原蛋白结合域融合技术的建立
  • 批准号:
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  • 批准号:
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  • 财政年份:
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白血病同种异体移植
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    8260361
  • 财政年份:
    2011
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    $ 7.25万
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Composite Allografting for Promoting Survival of Corneal Transplants
复合同种异体移植促进角膜移植的存活
  • 批准号:
    7878675
  • 财政年份:
    2009
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    $ 7.25万
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Composite Allografting for Promoting Survival of Corneal Transplants
复合同种异体移植促进角膜移植的存活
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增强同种异体移植后的抗肿瘤免疫力
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    $ 7.25万
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Augmenting Antitumor Immunity after Allografting
增强同种异体移植后的抗肿瘤免疫力
  • 批准号:
    8010394
  • 财政年份:
    2008
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Augmenting Antitumor Immunity after Allografting
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Augmenting Antitumor Immunity after Allografting
增强同种异体移植后的抗肿瘤免疫力
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    2008
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