Indoleamine 2, 3 dioxygenase signaling and function in Type 1 Diabetes

1 型糖尿病中吲哚胺 2、3 双加氧酶信号传导和功能

• 批准号: 7497430
• 负责人: Suparna A Sarkar
• 金额: $ 12.06万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-20 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7497430
• 关键词: Adenosine Diphosphate Ribose; Allogenic; Antioxidants; Apoptotic; Autoimmune Diseases; Autoimmune Process; Back; Biology; Catabolism; Cell Count; Cell Death; Cell Survival; Cell physiology; Cells; Cessation of life; Cyclic ADP-Ribose; Diabetes Mellitus; Dioxygenases; Effector Cell; Enzymes; Essential Amino Acids; Gene Expression Profiling; Gene Proteins; Genes; Growth; Human; Immune; In Vitro; Inbred NOD Mice; Individual; Inflammation; Inflammatory; Insulin-Dependent Diabetes Mellitus; Interferons; Interleukin-1; Interleukin-4; Islet Cell; Islets of Langerhans; Janus kinase; Kynurenine; Lead; Localized; Maintenance; Mediating; Messenger RNA; Molecular; Mus; N' -formylkynurenine; Nicotinamide adenine dinucleotide; Nitrous Oxide; Oxidation-Reduction; Oxygen; Oxygenases; Pancreas; Parasites; Pathogenesis; Pathway interactions; Picolinic Acids; Play; Polymerase Chain Reaction; Population; Principal Investigator; Proteins; Rate; Role; STAT protein; Sampling; Series; Signal Transduction; Signal Transduction Pathway; Superoxides; T-Lymphocyte; TNF gene; Therapeutic; Toxoplasma gondii; Transcriptional Regulation; Transplantation; Tryptophan; cell type; cytokine; cytotoxic; disorder control; feeding; human disease; hydroxyanthranilate; indoleamine; insight; islet; killings; methyl tryptophan; neoplastic cell; picolinic acid; programs; quinolinate; response

DESCRIPTION (provided by applicant): The loss of pancreatic (-cells in type 1A diabetes (TID) occurs principally through cell-mediated autoimmune attack though the precise mechanisms that result in the demise of an individual (-cells is unclear. Soluble cytokines clearly play an important role both in signaling between effector cells and can initiate defensive and or apoptotic responses in the target. Microarray gene expression profiling of human and mouse islets exposed to a series of pro-inflammatory cytokines have revealed a remarkable induction of Indoleamine 2, 3 dioxygenase (IDO) in islets in response to IFN(. IDO catalyzes the initial, rate-limiting step of Tryptophan (Trp) catabolism along the Kynurenine (Kyn) pathway. IDO protein was up-regulated and increased enzymatic activity of IDO was noted in the IFN(-treated islet samples. 1 (-methyl tryptophan (1 MT) and Interleukin 4 (IL 4) were able to inhibit the IDO specific activity in vitro. Immunohistochemically IDO was localized in more than one cell type in the islets. In addition, co exposure of IL1(, IFN( and TNF( to human islets resulted in induction of both IDO and inducible form of Nitrous oxide synthase (iNOS). We hypothesize that short term IDO activation may protect islets from cytotoxic damage through depletion of superoxides and maintenance of redox potential, and that the release of Trp metabolites such as 3-OH-Kyn, 3-hydroxyanthranilate, quinolinate and picolinic acid could provide bystander inhibition of immune cell function. In the longer term the various metabolites may feed back on the islets themselves and could ultimately lead to (-cell attrition. The current proposal focuses on the signal biology and function of IDO and the metabolites generated during the catabolism of Trp in the context of our hypotheses. Specifically we aim to 1) To investigate the JAK STAT signal transduction pathway involved in IDO induction in mouse and human islets. 2) Document the relationship between IDO and iNOS in islets during co-induction by cytokine cocktail (IL1( + IFN( + TNF() and its effect on islet cell survival. 3) Determine the effects of short and long-term activation of IDO by exploring the antioxidant activities of IDO and Trp metabolites on islet cell function and survival. The results will provide insight into the molecular mechanism of IDO signaling, modulation of IDO gene, and protein. More critically, its interaction with iNOS and other agents that can alter the cellular redox potential will better help us understand its immunoregulatory and antioxidant role in the context of an immune attack in TID. These studies should provide new insight into the pathogenesis of TID and develop new strategies for therapeutic treatment and control of the disease.

描述（由申请人提供）： The loss of pancreatic (-cells in type 1A diabetes (TID) occurs principally through cell-mediated autoimmune attack though the precise mechanisms that result in the demise of an individual (-cells is unclear. Soluble cytokines clearly play an important role both in signaling between effector cells and can initiate defensive and or apoptotic responses in the target. Microarray gene expression profiling of human and mouse暴露于一系列促炎性细胞因子的胰岛已经揭示了胰岛中吲哚胺2、3二氧酶（IDO）的显着诱导，响应于IFN（。IDO催化沿kynurenine（kynurenine）沿着kynurenine（kynrine）的最初，速率限制的步骤，以下是依次的。在IFN（ - 处理的胰岛样品）中指出。1（ - 甲基色氨酸（1 mT）和白介素4（IL 4）能够在体外抑制IDO特异性活性。免疫组织化学上的IDO被定位在胰岛中多种细胞类型中。此外，CO暴露于IL1（，IFN（和TNF）（人类胰岛导致诱导IDO和可诱导形式的一氧化二氮合酶（Inos）。我们假设短期IDO激活可能会保护胰岛可以保护胰岛通过超级氧化物的depoction and-weastion and trom of-of oferob的释放，并释放的损害，并释放3个释放，并释放了3个释放，以释放的释放，以释放的超氧释放，并确保释放，以释放的超氧释放，并确保释放的损害。 3-羟基含量，喹啉酸和picolinic酸可以在长期内抑制免疫细胞功能。 1）研究小鼠和人类胰岛中IDO诱导涉及的JAK STAT信号转导途径。 2）记录细胞因子鸡尾酒共同诱导过程中胰岛中IDO和INOS之间的关系（IL1（ + IFN（ + TNF（ + TNF（）及其对胰岛细胞存活的影响。 3）通过探索IDO和TRP代谢物对胰岛细胞功能和存活的抗氧化活性来确定IDO的短期和长期激活的影响。 结果将提供有关IDO信号传导，IDO基因调节和蛋白质的分子机制的见解。更重要的是，它与INOS和其他可以改变细胞氧化还原电位的药物的相互作用将更好地帮助我们理解其在TID中免疫攻击的背景下其免疫调节和抗氧化作用。这些研究应为TID的发病机理提供新的见解，并为治疗和控制疾病制定新的策略。