Targeting endothelial migration to prevent neovascularization

靶向内皮迁移以预防新血管形成

• 批准号: 9260074
• 负责人: Anne Christine Eichmann
• 金额: $ 41.63万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9260074
• 关键词: Adaptor Signaling Protein; Affect; Age related macular degeneration; Axon; Binding; Biological; Biology; Blindness; Blood Vessels; CDC42 gene; Cell Communication; Cell Proliferation; Cell Survival; Cells; Clinical Trials; Cornea; Cytoplasmic Tail; Data; Defect; Development; Diabetic Retinopathy; Disease; Edema; Endocytosis; Endothelial Cells; Event; Fibroblast Growth Factor; Genes; Genetic; Goals; Guanosine Triphosphate Phosphohydrolases; Hemorrhage; In Vitro; Industrialization; Injection of therapeutic agent; KDR gene; Lead; Leukocytes; Ligands; Link; Mediating; Modeling; Molecular; Mus; Oxygen; Pathway interactions; Patients; Pericytes; Peripheral; Phosphorylation Site; Pre-Clinical Model; Process; Recruitment Activity; Retinal Detachment; Retinal Diseases; Retinal Neovascularization; Role; Signal Pathway; Signal Transduction; Site; Testing; Therapeutic; Tissues; Treatment Factor; Vascular Diseases; Vascular Endothelial Growth Factors; Vision; Wound Healing; angiogenesis; blood vessel development; cell behavior; cell motility; cell type; diabetic patient; efficacy testing; experimental study; improved; in vivo; insight; interest; loss of function; matrigel; migration; mouse model; neovascular; neovascularization; novel; novel therapeutics; ocular neovascularization; patient subsets; prevent; public health relevance; receptor; response; retinal angiogenesis; success; therapeutic target

 DESCRIPTION (provided by applicant): The majority of severe vision loss in the US results from complications associated with retinal neovascularization in patients with ocular diseases, including diabetic retinopathy (DR) and Age- Related Macular Degeneration (AMD). These diseases are characterized by excessive angiogenesis, which promotes vascular leak leading to edema, hemorrhage and retinal detachment compromising vision. To date, the treatment of excessive angiogenesis relies largely on inhibition of a single factor, vascular endothelial growth factor (VEGF), with some therapeutic success. Clinical trials have shown that anti-VEGF treatment reduces angiogenesis in AMD and DR patients, indicating that anti-angiogenic treatment is a viable therapeutic option. However, treatments involve frequent intraocular injections, and a proportion of patients do not achieve vision improvement. Therefore, there is enormous therapeutic interest to develop treatments that enhance response to anti-VEGF agents and improve the lives of patients with ocular neovascular disease. We here identify the guidance molecule Slit2 as a requisite factor that promotes angiogenesis in addition to VEGF. Disruption of Slit2 function by temporally inducible deletion of the Slit2 gene, and combined deletion of its Robo1 and Robo2 receptors in ECs potently inhibits retinal neovascularization. These data lead us to test the hypothesis that blocking Slit2 signaling through Robo1 and 2 represents an alternative pathway to block excessive angiogenesis that may serve as a therapeutic target in conjunction with anti-VEGF treatment of AMD. Mechanistically, we will test the hypothesis that blocking of Slit2-Robo1/2 signaling improves efficacy of anti-VEGF treatment by selectively targeting EC migration and define the signaling pathways regulating this process. Our studies will provide the first comprehensive examination of Slit-Robo1/2-mediated angiogenesis in ocular neovascularization, determine its biological significance and define the molecular and cellular basis of Slit signaling through Robo1/2 signaling. Understanding these mechanisms will provide insight into signaling events required for polarized endothelial cell migration during neovascularization, which is a fundamental, yet poorly understood event in vascular biology. The ultimate goal of our proposal is to develop new therapies to prevent intraocular vascular disease.

 描述（由适用提供）：美国的大部分严重视力丧失是由于眼部疾病患者（包括糖尿病性视网膜病）（DR）和与年龄相关的黄斑变性（AMD）相关的视网膜新血管形成并发症。这些疾病的特征是过度血管生成，该疾病促进了血管渗漏，导致湿气，出血和视网膜脱离损害视力。迄今为止，过度血管生成的治疗在很大程度上取决于对单一因素，血管内皮生长的抑制 因素（VEGF），并获得一些治疗成功。临床试验表明，抗VEGF治疗减少了AMD和DR患者的血管生成，表明抗血管生成治疗是一种可行的治疗选择。但是，治疗经常涉及眼内注射，并且一定比例的患者无法改善视力。因此，开发疗法具有巨大的治疗兴趣，以增强对抗VEGF药物的反应并改善眼部新生血管疾病患者的生活。在这里，我们将指导分子裂隙2确定为促进VEGF以外血管生成的必要因素。 SLIT2基因的暂时诱导缺失以及EC中其ROBO1和ROBO2受体的结合缺失，可能会抑制残留的新血管形成。这些数据导致我们检验以下假设：通过ROBO1和2阻止SLIT2信号传导代表了阻断过量血管生成的另一种途径，该途径可以作为治疗靶标，并结合AMD的抗VEGF处理。从机械上讲，我们将测试以下假设：SLIT2-ROBO1/2信号的阻断通过选择性靶向EC迁移并定义了调节此过程的信号通路，从而提高了反VEGF处理的效率。我们的研究将对眼部新生血管形成中的裂隙 - 摩布1/2介导的血管生成进行首次全面检查，确定其生物学，并通过ROBO1/2信号定义裂隙信号传导的分子和细胞基础。了解这些机制将提供对神经血管化期间极化内皮细胞迁移所需的信号传导事件的洞察力，这是血管生物学中的基本但知之甚少的事件。我们提案的最终目标是开发新的疗法，以预防人数血管疾病。