Role of toll-like receptor signaling in retinal ischemia

Toll样受体信号传导在视网膜缺血中的作用

• 批准号: 8272305
• 负责人: Dmitry V Ivanov
• 金额: $ 36.4万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8272305
• 关键词: Adaptor Signaling Protein; Adhesions; Animals; Anterior Ischemic Optic Neuropathy; Astrocytes; Blindness; Blood; Cell Death; Cells; Clinical; Data; Detection; Development; Diabetic Retinopathy; Disease; Endothelial Cells; Event; Foundations; Future; Glaucoma; Immigrant; Immune; Immune response; Immune system; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Injury; Ischemia; Ischemic Neuronal Injury; Knowledge; Lead; Leukocytes; Ligands; Literature; MAPK14 gene; MAPK8 gene; Mediating; Microglia; Molecular; NADPH Oxidase; Necrosis; Neuroglia; Neurons; Nitric Oxide Synthase; Optic Nerve Injuries; Outcome; Oxidative Stress; Pathogenesis; Pathologic; Pathology; Pathway interactions; Patients; Pattern; Permeability; Play; Production; Publishing; Receptor Signaling; Recombinants; Reperfusion Injury; Reperfusion Therapy; Research; Retina; Retinal; Retinal Diseases; Retinal Ganglion Cells; Role; Series; Signal Transduction; Staging; Testing; Toll-like receptors; Toxic effect; Transcription Factor AP-1; Visual impairment; caspase-3; cell injury; chemokine; cytokine; deprivation; effective therapy; extracellular; improved; indium arsenide; injured; innovation; macrophage; neuron loss; neuroprotection; novel therapeutic intervention; pathogen; prevent; receptor; research study; response; retina blood vessel structure; retinal damage; retinal ischemia; therapeutic development; therapeutic target; toll-like receptor 4; tool

DESCRIPTION (provided by applicant): Ischemia-reperfusion (IR) injury is implicated in a large array of pathological conditions in the retina including glaucoma, diabetic retinopathy, anterior ischemic optic neuropathy and traumatic optic neuropathy. Thus, understanding the events involved in ischemic neuronal injury can provide us with clinically effective treatments for many retinal diseases. Although the cause of this injury is multifactorial, increasing experimental evidence suggests an important role for the innate immune system in initiating the inflammatory cascade leading to detrimental/deleterious changes in retinal function. Toll-like receptors (TLRs) are recognized as one of the main contributors to pathogen-induced inflammation and, more recently, injury-induced inflammation. Endogenous ligands liberated from injured/necrotic cells can activate TLRs, initiating an inflammatory response even in the absence of pathogens. Our published results indicate that the level of endogenous ligands for toll- like receptor 4 (TLR4) increases in retinal IR and, through activation of TLR4, are involved in retinal damage and inflammation triggered by ischemic injury. Importantly, our preliminary results suggest that the mechanisms mediating ischemic damage in the retina are facilitated not only by inflammation induced by astrocytes, microglia, or infiltrating immune cells, but also by activation of TLR4 in retinal ganglion cells (RGCs) themselves. However, the exact mechanism of TLR4 signaling-induced inflammation and damage after retinal IR injury remains unknown. In this project we hypothesize that TLR4 signaling plays a significant role in the pathogenesis of retinal IR injury by directly and/or indirectly contributing to the injury of RGCs. This hypothesis will be tested ina series of experiments outlined in the following specific aims: 1) to determine whether TLR4 coordinates the immune response of the retina to IR injury~ 2) to determine whether silencing of TLR4 signaling reduces blood retinal permeability and infiltration of leukocytes in the ischemic retina~ 3) to determine whether TLR4-mediated signals directly injure RGCs~ 4) to define the role of TLR4 ligands in the post-ischemic retina. Completion of these specific aims could lead to the discovery of innovative strategies to help prevent the loss of vision in patients suffering fro retinal ischemia, as selective targeting of both TLR4 and its ligands may be more effective for the development of therapeutic tools to prevent IR injury than targeting the intracellular pathways. PUBLIC HEALTH RELEVANCE: Ischemia-reperfusion (IR) injury of the retina is implicated in a large array of pathological conditions in which inflammation is a hallmark of disease. Toll-like receptors (TLRs) are recognized as one of the main contributors to pathogen-induced inflammation and, more recently, injury-induced inflammation. A greater understanding of the role of TLRs in retinal IR injury may aid in the development of specific TLR-targeted therapeutics to treat these conditions in the retina, which may be more effective for the development of therapeutic tools to prevent IR injury than targeting the intracellular pathways.

描述(申请人提供)：缺血-再灌注(IR)损伤涉及视网膜的一系列病理情况，包括青光眼、糖尿病视网膜病变、前部缺血性视神经病变和外伤性视神经病变。因此，了解缺血性神经元损伤所涉及的事件可以为我们提供临床有效的治疗方法。 很多视网膜疾病。虽然这种损伤的原因是多因素的，但越来越多的实验性 有证据表明，先天免疫系统在启动炎性级联反应中发挥了重要作用，从而导致视网膜功能的有害/有害变化。Toll样受体(TLRs)被认为是病原体诱导炎症的主要因素之一，最近又被认为是损伤诱导炎症的主要因素之一。从损伤/坏死细胞中释放出来的内源性配体可以激活TLRs，即使在没有病原体的情况下也能启动炎症反应。我们已发表的结果表明，Toll样受体4的内源性配体水平在视网膜IR中增加，并通过激活TLR4参与由缺血损伤引发的视网膜损伤和炎症。重要的是，我们的初步结果表明，介导视网膜缺血性损伤的机制不仅是由星形胶质细胞、小胶质细胞或浸润性免疫细胞诱导的炎症，而且还通过激活视网膜神经节细胞(RGCs)本身的TLR4来促进。然而，TLR4信号诱导视网膜IR损伤后炎症和损伤的确切机制仍不清楚。在本项目中，我们假设TLR4信号在视网膜IR损伤的发病机制中起重要作用，直接和/或间接促进RGCs的损伤。这一假说将通过下列具体目标的一系列实验来验证：1)确定TLR4是否协调视网膜对IR损伤的免疫反应~2)确定沉默TLR4信号是否能降低缺血视网膜中的血视网膜通透性和白细胞的渗透~3)确定TLR4介导的信号是否直接损伤RGC)以确定TLR4配体在缺血后视网膜中的作用。完成这些特定的目标可能会导致发现有助于预防视网膜缺血患者视力丧失的创新策略，因为选择性靶向TLR4及其配体可能比靶向细胞内通路更有效地开发预防IR损伤的治疗工具。 公共卫生相关性：视网膜的缺血-再灌注(IR)损伤与多种病理情况有关，其中炎症是疾病的标志。Toll样受体(TLRs)被认为是病原体诱导炎症的主要因素之一，最近又被认为是损伤诱导炎症的主要因素之一。进一步了解TLRs在视网膜IR损伤中的作用可能有助于开发针对TLR的特异性治疗药物来治疗视网膜中的这些疾病，这对于开发预防IR损伤的治疗工具可能比针对细胞内通路更有效。