NITRIC OXIDE AND INSULIN IN ISLET TRANSPLANTATION

胰岛移植中的一氧化氮和胰岛素

• 批准号: 6177536
• 负责人: CHARLES D MILLS
• 金额: $ 20.74万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-09-15 至 2001-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6177536
• 关键词: RNase protection assay; autologous transplantation; blood glucose; cell type; diabetes mellitus; flow cytometry; gene targeting; genetically modified animals; homologous transplantation; hypoglycemia; insulin; laboratory mouse; laboratory rat; macrophage; nitric oxide; nitric oxide synthase; pancreatic islet transplantation; tissue /cell culture; transplant rejection; transplantation immunology

The goal of this investigation is to increase the success of clinical islet transplantation. Two interrelated hypotheses are put forth to achieve this goal. First, Nitric Oxide (NO) is postulated to be a prime mediator of islet dysfunction. Second, a previously unrecognized ability of insulin to decrease NO production is proposed to explain its islet-protective activity. Both of these hypotheses will be tested directly by focusing the experiments in this investigation on the use of inducible Nitric Oxide Synthase "knockout" mice (iNOS-/-). Specific Aim I will determine the role of macrophage NO in islet graft rejection. Based on preliminary and published results from this laboratory, NO is proposed to inhibit islets in 2 "waves": an early wave that occurs 1-2 days posttransplant of syngeneic or allogeneic islets is responsible for early islet dysfunction. A second wave NO-mediated islet dysfunction is proposed to occur during classical allograft rejection. The early wave will be investigated by comparing syngeneic islet function in diabetic iNOS-/- and iNOS-/+ mice; the second wave will be investigated using allogeneic islets in these hosts. Inhibitors of NO will then be used to determine how to best increase islet function. Preliminary and published evidence from this laboratory suggests that inhibiting NO in a clinically applicable way does increase the success of islet transplantation. Islets will be implanted in the intraperitoneal cavity in this investigation because intragraft NO production and allograft rejection responses can readily be followed at this site. Mice will be the primary species used because, like humans, they are "low" producers of NO; rats will be used in selected experiments because of their larger size. Specific Aim II will determine the mechanism by which insulin promotes islet function. A dominant paradigm has been that insulin allows transplanted beta-cells to "rest". However, preliminary evidence indicates that insulin administration to diabetic mice or rats decreases macrophage iNOS mRNA expression and NO production. Therefore, specific experiments will again compare iNOS- /- and iNOS-/+ mice to directly test the hypothesis that the islet- protective activity of insulin results from decreasing NO production. Finally, hyperglycemic clamps will be employed to maintain hyperglycemia in order to determine if the islet-protective activity of insulin depends on its ability to lower blood glucose. The results of this investigation should provide important new information that will increase the success of clinical islet transplantation as well as providing basic information on what role NO plays in rejection of cell transplants, and how NO production is regulated by insulin.

本研究的目的是提高临床胰岛的成功率

项目成果

Insulin down-regulates the inducible nitric oxide synthase pathway: nitric oxide as cause and effect of diabetes?

• DOI: 10.4049/jimmunol.159.11.5329
• 发表时间: 1997-12
• 期刊: Journal of immunology
• 影响因子: 4.4
• 作者: R. Stevens;D. Sutherland;J. Ansite;M. Saxena;T. Rossini;B. Levay-Young;B. Hering;C. Mills

Augmentation of an antitumor CTL response In vivo by inhibition of suppressor macrophage nitric oxide.

• DOI: 10.4049/jimmunol.163.11.5877
• 发表时间: 1999-12
• 期刊: Journal of immunology
• 影响因子: 4.4
• 作者: Marianne Medot-Pirenne;M. Heilman;Malinee Saxena;Patricia E. McDermott;Charles D. Mills