Total pancreatectomy and islet autotransplantation (IAT) is safe and effective in the management of intractable pain associated with chronic pancreatitis. A major problem associated with IAT is that the number of islets available for transplant is compromised by a severely diseased and fibrotic pancreas. Moreover, as many as 50-60% of islet cells undergo apoptosis at 2-3 days after intraportal transplantation when transplantation associated stressors (hypoxia, nutrient deprivation, reactive oxygen species, proinflammation cytokines) are induced during harvesting, isolation, and implantation of the islet cell mass. Although the quality-of-life parameters are significantly improved in our IAT patients, only 25% of patients become insulin independent (compared to 80% patients with normoglycemia before pancreatectomy). Strategies that produce more robust islets to resist stressors that induce cell apoptosis are an appealing and promising method to improve the efficiency of human IAT. Over the past 10 years we have focused on exploring strategies that can improve islet/ cell survival and function to treat patient with type-1 diabetes in the settingof allogeneic transplantation. Our novel findings indicate that exposing islets to low doses of carbon monoxide (CO, gaseous or dissolved in solutions) to the islet donor, or isolated islets, can protect those islets from stress-induced apoptosis and immune rejection after transplantation. Further study indicates that CO exposure to islet donor up-regulates expression of PPAR?, a transcriptional factor, in isolated islets. Donor treatment with PPAR? agonists leads to long-term (>100 days) survival of transplanted islets in a major mismatch islet transplantation model without any additional treatments. Islet autografts suffer from similar injuries as allograft and are spared the additional complexities of immune rejection response after transplantation. Thus, strategies such as PPAR? activation and CO exposure that can protect human islets from stress will bring immediate benefit to patients with chronic pancreatitis receiving an IAT and potentially serve as a platform on which to address the more complex allogeneic islet cell transplantation. In this study, we will test the hypothesis that stress-induced apoptosis of post IAT islets can be minimized leading to increased survival and function by harvesting islets in a CO-rich environment and/or PPAR? induction is isolated islets. Our state-of-the-art cGMP facility that undertakes IAT on a regular basis, our strong clinical and research team, clinical tral support, clinical trial nursing, clinical facilities, current patient pool and the biostatistics suport at MUSC offers powerful platform that can readily translate research finding from bench to bedside. Once the study is completed, it promises to advance the field of islet transplantation forward.

Public Health Relevance

The major goal of this grant is to apply effective interventional protocols developed in animal models to minimize surgical diabetes in patients with chronic pancreatitis who undergo total pancreatectomy with islet auto-transplantation. If successful, our study will significantly advance the field of islet transplantation going forward.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21DK097544-02
Application #
8788520
Study Section
Special Emphasis Panel (ZRG1-EMNR-K (80))
Program Officer
Arreaza-Rubin, Guillermo
Project Start
2014-01-01
Project End
2015-12-31
Budget Start
2015-01-01
Budget End
2015-12-31
Support Year
2
Fiscal Year
2015
Total Cost
$168,187
Indirect Cost
$55,687
Name
Medical University of South Carolina
Department
Surgery
Type
Schools of Medicine
DUNS #
183710748
City
Charleston
State
SC
Country
United States
Zip Code
29403
Kim, Do-Sung; Song, Lili; Wang, Jingjing et al. (2018) GRP94 Is an Essential Regulator of Pancreatic ?-Cell Development, Mass, and Function in Male Mice. Endocrinology 159:1062-1073
Wang, Hongjun; Strange, Charlie; Nietert, Paul J et al. (2018) Autologous Mesenchymal Stem Cell and Islet Cotransplantation: Safety and Efficacy. Stem Cells Transl Med 7:11-19
Kim, Do-Sung; Song, Lili; Wang, Jingjing et al. (2018) Carbon Monoxide Inhibits Islet Apoptosis via Induction of Autophagy. Antioxid Redox Signal 28:1309-1322
Dong, H; Zhang, Y; Wang, J et al. (2017) Regulator of G protein signaling 2 is a key regulator of pancreatic ?-cell mass and function. Cell Death Dis 8:e2821
Wang, Jingjing; Wang, Hongjun (2017) Oxidative Stress in Pancreatic Beta Cell Regeneration. Oxid Med Cell Longev 2017:1930261
Sun, Zhen; Gou, Wenyu; Kim, Do-Sung et al. (2017) Adipose Stem Cell Therapy Mitigates Chronic Pancreatitis via Differentiation into Acinar-like Cells in Mice. Mol Ther 25:2490-2501
Song, Lili; Sun, Zhen; Kim, Do-Sung et al. (2017) Adipose stem cells from chronic pancreatitis patients improve mouse and human islet survival and function. Stem Cell Res Ther 8:192
Wang, Jingjing; Sun, Zhen; Gou, Wenyu et al. (2017) ?-1 Antitrypsin Enhances Islet Engraftment by Suppression of Instant Blood-Mediated Inflammatory Reaction. Diabetes 66:970-980
Zhang, Yanqing; Fava, Genevieve E; Wang, Hongjun et al. (2016) PAX4 Gene Transfer Induces ?-to-? Cell Phenotypic Conversion and Confers Therapeutic Benefits for Diabetes Treatment. Mol Ther 24:251-260
Cao, Mingjun; Pan, Qingjie; Dong, Huansheng et al. (2015) Adipose-derived mesenchymal stem cells improve glucose homeostasis in high-fat diet-induced obese mice. Stem Cell Res Ther 6:208

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