CELLULAR MECHANISMS OF PATHOLOGICAL RETINAL NEOVASCULARIZATION

病理性视网膜新生血管化的细胞机制

• 批准号: 10611949
• 负责人: Nikhlesh Kumar Singh
• 金额: $ 38.5万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10611949
• 关键词: Abbreviations; Adult; Affect; Age related macular degeneration; Angiogenic Factor; Angiogenic Proteins; Apoptosis; Blindness; Blood Vessels; CASP1 gene; CASP3 gene; Caspase; Cells; Child; Data; Developed Countries; Development; Diabetes Mellitus; Diabetic Retinopathy; Disease; Disintegrins; Down-Regulation; Elderly; Endothelial Cells; Endothelium; Exudative age-related macular degeneration; Fibrosis; Functional disorder; Gene Silencing; Genetic; Growth; Hematopoietic stem cells; Hypoxia; Impairment; Inflammasome; Inflammation Mediators; Inflammatory; Injections; Interleukins; Ischemia; Knockout Mice; Knowledge; Lasers; Macrophage; Mediating; Membrane; Metalloproteases; Microglia; Modeling; Mus; Myelogenous; Oxygen; Pathologic; Pathologic Neovascularization; Patients; Pattern; Phase; Phenotype; Production; Proliferating; Proteins; Publishing; RNA Interference; Reporting; Research; Retina; Retinal Detachment; Retinal Diseases; Retinal Neovascularization; Retinopathy of Prematurity; Role; Signal Transduction; Surface; Testing; Therapeutic; Thrombospondins; Traction; Tumorigenicity; Vascular Permeabilities; Vascularization; Visual impairment; Vitreous humor; age group; angiogenesis; bevacizumab; cadherin 5; conditional knockout; connective tissue growth factor; design; improved; light transmission; migration; mouse model; neovascularization; novel; novel therapeutic intervention; pharmacologic; proliferative diabetic retinopathy; receptor; recruit; response; retinal angiogenesis; retinal damage; tissue regeneration; wound healing; Abbreviations; Adult; Affect; Age related macular degeneration; Angiogenic Factor; Angiogenic Proteins; Apoptosis; Blindness; Blood Vessels; CASP1 gene; CASP3 gene; Caspase; Cells; Child; Data; Developed Countries; Development; Diabetes Mellitus; Diabetic Retinopathy; Disease; Disintegrins; Down-Regulation; Elderly; Endothelial Cells; Endothelium; Exudative age-related macular degeneration; Fibrosis; Functional disorder; Gene Silencing; Genetic; Growth; Hematopoietic stem cells; Hypoxia; Impairment; Inflammasome; Inflammation Mediators; Inflammatory; Injections; Interleukins; Ischemia; Knockout Mice; Knowledge; Lasers; Macrophage; Mediating; Membrane; Metalloproteases; Microglia; Modeling; Mus; Myelogenous; Oxygen; Pathologic; Pathologic Neovascularization; Patients; Pattern; Phase; Phenotype; Production; Proliferating; Proteins; Publishing; RNA Interference; Reporting; Research; Retina; Retinal Detachment; Retinal Diseases; Retinal Neovascularization; Retinopathy of Prematurity; Role; Signal Transduction; Surface; Testing; Therapeutic; Thrombospondins; Traction; Tumorigenicity; Vascular Permeabilities; Vascularization; Visual impairment; Vitreous humor; age group; angiogenesis; bevacizumab; cadherin 5; conditional knockout; connective tissue growth factor; design; improved; light transmission; migration; mouse model; neovascularization; novel; novel therapeutic intervention; pharmacologic; proliferative diabetic retinopathy; receptor; recruit; response; retinal angiogenesis; retinal damage; tissue regeneration; wound healing

Retinal neovascularization is an ocular manifestation of diabetes, retinopathy of prematurity and age-related macular degeneration, which leads to vision loss. Despite the use of anti-VEGF and laser treatments, progression of retinal neovascularization continues to cause blindness. The development of new therapeutic approaches against retinal neovascularization is limited, because of lack of knowledge about its pathophysiology. Retinal neovascularization is characterized by production of several angiogenic factors, with consequential growth of aberrant new blood vessels on retinal surface that interferes with light transmission and results in vision loss. An elevated levels of inflammation and inflammatory mediators have been observed in retinas or vitreous isolated from patients with pathological retinal neovascularization. Therefore, the ability to modulate inflammation and inflammatory mediators and thereby selectively modulating aberrant retinal neovascularization, would be a great strategy in the treatment of pathological retinal neovascularization. To understand the functional significance of inflammation and inflammatory mediators in retinal neovascularization, we performed preliminary studies using mouse model of oxygen-induced retinopathy. Our preliminary studies suggest a predominant role caspase-3 and inflammatory caspase (caspase-1) in retinal neovascularization. Our primary hypothesis to be tested is novel and fills some voids in our understanding about pathological neoangiogenesis. The specific aims of our proposed studies are to test the hypotheses that (1) IL-33 and caspases mediates hypoxia-induced pathological retinal neovascularization, (2) IL-33/ST2L mediated ADAMTS10 or VE-cadherin activation regulates sprouting angiogenesis and vessel branching, and (3) IL-33/ST2L signaling regulates the functional polarization of inflammatory cells to M2-like macrophages in hypoxic retina. Achieving these specific aims will elucidate the mechanisms through which various inflammatory molecules affect retinal neovascularization and open up a new line of understanding about the pathophysiology of various proliferative retinopathies. In addition, the proposed research will certainly contribute to the development of new therapeutic strategies against proliferative diabetic retinopathy and retinopathy of prematurity.

视网膜新血管形成是糖尿病的眼部表现，早产性视网膜病变和与年龄有关 黄斑变性，导致视力丧失。尽管使用了抗VEGF和激光治疗，但 视网膜新血管形成的进展继续引起失明。新治疗的发展 反对视网膜新血管形成的方法是有限的，因为缺乏对其的知识 病理生理学。视网膜新血管形成的特征是产生几种血管生成因子，并具有 视网膜表面上异常新血管的相应生长会干扰光传输 并导致视力丧失。在 从病理视网膜新血管形成患者中分离出视网膜或玻璃体。因此，能够 调节炎症和炎症介质，从而选择性调节视网膜异常 新血管形成将是治疗病理性视网膜新血管形成的重要策略。到 了解视网膜炎症和炎症介质的功能意义 新血管形成，我们使用氧诱导的视网膜病小鼠模型进行了初步研究。我们的 初步研究表明，在视网膜中具有主要作用caspase-3和炎症caspase（caspase-1） 新血管形成。我们要测试的主要假设是新颖的，并在我们的理解中填补了一些空白 关于病理新血管生成。我们提出的研究的具体目的是检验假设 （1）IL-33和caspase介导缺氧诱导的病理视网膜新血管形成，（2）IL-33/ST2L 介导的ADAMTS10或VE-钙粘蛋白激活调节发芽的血管生成和血管分支，并且 （3）IL-33/ST2L信号传导调节炎症细胞对M2样巨噬细胞的功能极化 缺氧视网膜。实现这些特定目标将阐明各种机制 炎症分子会影响视网膜新血管形成，并为 各种增殖性视网膜病的病理生理。此外，拟议的研究肯定会 有助于制定针对增生性糖尿病性视网膜病和的新治疗策略 早产的视网膜病变。