Role of toll-like receptor signaling in retinal ischemia

项目摘要 缺血-再灌注（IR）损伤与视网膜中的大量病理状况有关，包括 青光眼、糖尿病视网膜病变、前部缺血性视神经病变和创伤性视神经病变。因此，在本发明中， 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 许多视网膜疾病。虽然这种损伤的原因是多因素的，但越来越多的实验证据表明， 表明先天免疫系统在引发炎症级联反应中起重要作用， 视网膜功能的有害/有害变化。Toll样受体（TLR）被认为是一种 病原体诱导的炎症和最近的损伤诱导的炎症的主要贡献者。 从损伤/坏死细胞中释放的内源性配体可以激活TLR，引发炎症反应 即使没有病原体。我们发表的结果表明，内源性配体的水平，为toll- 类受体4（TLR 4）在视网膜IR中增加，并通过TLR 4的活化参与视网膜损伤 以及由缺血性损伤引发的炎症。重要的是，我们的初步结果表明， 视网膜中介导缺血性损伤的机制不仅由炎症诱导， 星形胶质细胞、小胶质细胞或浸润性免疫细胞，而且还通过激活视网膜神经节细胞（RGC）中的TLR 4 自己然而，TLR 4信号转导诱导的视网膜损伤后炎症和损伤的确切机制尚不清楚。 IR损伤仍然未知。在这个项目中，我们假设TLR 4信号传导在细胞凋亡中起着重要作用。 通过直接和/或间接促进RGC的损伤，可导致视网膜IR损伤的发病机制。这一假设 将在以下具体目标中概述的一系列实验中进行测试：1）确定TLR 4是否 协调视网膜对IR损伤的免疫应答~ 2）以确定TLR 4信号转导的沉默是否 减少缺血性视网膜中的血视网膜渗透性和白细胞浸润~ 3）以确定是否 TLR 4介导的信号直接损伤RGCs~ 4）以确定TLR 4配体在缺血后视网膜中的作用。 这些具体目标的完成可能会导致创新战略的发现，以帮助防止损失 在患有视网膜缺血的患者中，选择性靶向TLR 4及其配体可能是 更有效的治疗工具的发展，以防止IR损伤比靶向细胞内 途径。

PROJECT SUMMARY 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 in a 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 from 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.