The Pathomechanistic Role of Endothelial IDO in proliferative Retinopathy

内皮 IDO 在增殖性视网膜病变中的病理机制作用

• 批准号: 8824075
• 负责人: HELEN CHRISTOU
• 金额: $ 25.41万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-01-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8824075
• 关键词: Address; Adult; Adverse drug effect; Adverse effects; Age; Animal Model; Area; Biological; Biology; Blindness; Blood Vessels; Cell Line; Cellular biology; Chemicals; Child; Clinical; Clinical Treatment; Clinical Trials; Collaborations; Data; Diabetes Mellitus; Diabetic Retinopathy; Dioxygenases; Disease; Endothelial Cells; Endothelium; Enzyme Inhibition; Enzymes; Formates; Future; Genes; Goals; Growth; Hospitals; Human; In Vitro; Incidence; Indoles; Intervention; Kynurenine; Light; Link; Malignant Neoplasms; Mediating; Modeling; Molecular; Molecular Weight; Mus; Outcome; Oxygen; Pathologic; Pathologic Neovascularization; Pathway interactions; Patients; Pharmaceutical Preparations; Phase I Clinical Trials; Play; Premature Birth; Prevention; Production; Proteins; Quality of life; Refractory; Research; Retinal; Retinal Diseases; Retinal Neovascularization; Retinopathy of Prematurity; Role; Safety; Scientist; Series; Signal Pathway; Signal Transduction; Sleeping Beauty; Solid Neoplasm; Testing; Therapeutic; Tryptophan; Tube; Up-Regulation; Vascular Endothelial Cell; Vascular Endothelial Growth Factors; Vision; Woman; Work; angiogenesis; base; clinical practice; gain of function; improved; in vivo; indoleamine; inhibitor/antagonist; medical schools; migration; neovascularization; novel; novel strategies; overexpression; prevent; proliferative diabetic retinopathy; public health relevance; pup; research study; response; retinal angiogenesis; small molecule; stem; therapeutic target; transgene expression

DESCRIPTION (provided by applicant): Proliferative retinopathy (PR), which includes retinopathy of prematurity (ROP) and proliferative diabetic retinopathy (DR), represent a leading cause of blindness in both children and working-age adults. Although PR is characterized by pathological retinal vascular overproliferation or neovascularization, therapies aimed at specifically inhibiting production of vascular endothelial growth factor (VEGF) have failed to consistently improve clinical outcomes. This observation clearly indicates that additional molecular factors/pathways contribute to pathological retinal neovascularization in PR and may thus be viable therapeutic targets. In this regard, we became intrigued by our preliminary finding that strong indoleamine-2,3-dioxygenase (IDO) expression is present in the vitreous of patients with DR as well as in the endothelium of retinal neovessels from mouse pups undergoing oxygen-induced retinopathy (OIR). Further, in in vitro experiments, we found that up-regulation of IDO endows the vascular endothelial cells (ECs) with enhanced capacity for proliferation, migration and tube formation independently of VEGF. In light of these novel findings we hypothesize that that endothelial IDO possesses pro-angiogenic activity, and that targeted inhibition of this enzyme will block the pathological retinal angiogenesis/neovascularization in PR. To test this hypothesis, we will use a number of unique approaches, which include a stable IDO-overexpressing retinal vascular EC line and the Sleeping- Beauty (SB)-based nonviral gene integrating strategy capable of long-lasting human IDO (hIDO) transgene expression within retinal ECs in vivo. In Specific Aim 1, we will evaluate the pro-angiogenic activity of endothelial IDO in vitro and in vivo, with a focus on the the molecular mechanism(s) behind IDO-induced phenotypic switching of retinal ECs from a normal to a pro-angiogenic state. In Specific Aim 2, we will examine the therapeutic potential of pharmacological inhibition of retinal endothelial IDO in the prevention of experimental PR. In these studies, we seek to achieve the therapeutic goal using selective IDO inhibitor 1-metheyl-DL-tryptophan (1-mT), a small molecular chemical (molecular weight 218) that can be orally or intraperitoneally administered and is currently used in anti-cancer clinical trials with satisfactory safety profile. Taken together, this proposal addresses a critical scientific gap in the treatment of PR, and if proven effective, may be fast-tracked to a phase 1 clinical trial.

描述（由申请人提供）：增殖性视网膜病（PR），包括早产儿视网膜病（ROP）和增殖性糖尿病视网膜病（DR），是导致儿童和工作年龄成人失明的主要原因。尽管 PR 的特点是病理性视网膜血管过度增殖或新生血管形成，但旨在特异性抑制血管内皮生长因子 (VEGF) 产生的治疗未能持续改善临床结果。这一观察结果清楚地表明，其他分子因素/途径有助于 PR 中的病理性视网膜新生血管形成，因此可能是可行的治疗靶点。在这方面，我们的初步发现引起了我们的兴趣，即 DR 患者的玻璃体以及经历氧诱导性视网膜病变的小鼠幼崽的视网膜新生血管内皮中存在强吲哚胺-2,3-双加氧酶 (IDO) 表达（奥伊尔）。此外，在体外实验中，我们发现IDO的上调赋予血管内皮细胞（EC）独立于VEGF的增殖、迁移和管形成的能力增强。根据这些新发现，我们假设内皮 IDO 具有促血管生成活性，并且靶向抑制该酶将阻断 PR 中的病理性视网膜血管生成/新血管形成。为了检验这一假设，我们将使用许多独特的方法，其中包括稳定的 IDO 过表达视网膜血管 EC 系和基于睡美人 (SB) 的非病毒基因整合策略，能够持久人类 IDO (hIDO) 转基因体内视网膜 EC 内的表达。在具体目标 1 中，我们将评估内皮细胞的促血管生成活性。 IDO 体外和体内研究，重点关注 IDO 诱导的视网膜 EC 表型从正常状态转变为促血管生成状态背后的分子机制。在具体目标 2 中，我们将研究视网膜内皮 IDO 的药物抑制在预防实验性 PR 中的治疗潜力。在这些研究中，我们寻求使用选择性 IDO 抑制剂 1-甲基-DL-色氨酸 (1-mT) 来实现治疗目标，这是一种小分子化学物质（分子量 218），可以口服或腹膜内给药，目前用于抗-具有令人满意的安全性的癌症临床试验。总而言之，该提案解决了 PR 治疗中的一个关键科学差距，如果被证明有效，可能会快速进入一期临床试验。