Targeting Sigma 1 receptor as a novel therapy for limiting neurovascular injury in ROP

项目总结 早产儿视网膜病变(ROP)是导致儿童失明的主要原因。早期ROP的一个关键方面 是生理性视网膜血管发育的停滞。视网膜无血管与随后的低氧 导致增殖性致盲新生血管(NV)。缺血导致视网膜细胞功能障碍和 不可逆转的细胞损伤。新城疫会加剧视力恶化。然而，目前的临床护理标准 靶向异常的视网膜NV并没有改善，甚至可能损害视力。这里面的驾驶概念 建议为细胞存活、血管修复和血管重建创造良好的视网膜环境 缺血性视网膜。多种视网膜细胞类型参与形成视网膜环境，包括血管 内皮细胞、视网膜髓系细胞/小胶质细胞/巨噬细胞和神经细胞 如视网膜感光细胞(PRCs)和视网膜神经节细胞(RGCs)。潜在的机制 对于这些，细胞和分子的活动仍然没有明确的定义。Sigma 1受体(Sigma 1 R)，一种独特的 分子伴侣，提供了一种新的方法来有利地改善疾病下的视网膜环境 各州。Sig1R的激活对缺血视网膜的两个主要方面提供保护：氧化 压力和炎症。PI之前的研究表明，Sig1R对视网膜有强大的神经保护作用 视网膜神经退行性疾病。Sig1R激活对视网膜神经元有明显的神经保护作用 包括区域中心和区域中心。PI的最新独立研究探索了Sig1R在 视网膜血管疾病，包括ROP。PI的初步数据显示：i)Sig1R由其激活 配基()-五唑碱(()-PTZ)对氧诱导的无血管和NV有明显的保护作用 视网膜病变(OIR，ROP模型)；II)()-PTZ给药显著挽救受损的视功能 OIR小鼠；III)()-PTZ治疗抑制OIR中促炎因子和促血管生成因子的释放 视网膜；iv)Sig1R基因敲除延迟出生后第3天的视网膜血管发育。下一步评估 这一前景看好的双功能(血管和神经元)治疗潜力将成为这部新书的特征 Sig1R在OIR模型视网膜正常血管发育和血管损伤中的作用 确定Sig1R在其视网膜重编程中调制/靶向哪些细胞类型/分子 OIR对缺血的反应。我建议检验Sig1R作为一种新的密钥调节器的假设 OIR患者正常的视网膜血管发育和神经血管损伤，通过促进 通过抑制促炎症和促血管生成因子修复小胶质细胞/巨噬细胞，并提供 治疗ROP的一种新的神经血管疗法。我们提出了三个具体目标。1)描述Sig1R的角色 在正常视网膜血管发育和血管损伤的OIR模型中。2)检验假设 Sig1R通过抑制促炎症和促进修复的RMC来限制血管损伤 促血管生成因子。3)验证Sig1R在ROP过程中对神经保护起关键作用的假设。

PROJECT SUMMARY Retinopathy of prematurity (ROP) is a leading cause of childhood blindness. A pivotal aspect of early ROP is an arrest in physiologic retinal vascular development. The retinal avascularity and consequent hypoxia leads to proliferative blinding neovascularization (NV). Ischemia induces retinal cell dysfunction and irreversible cell damage. NV aggravates vision deterioration. However, current clinical standard-of-care targeting abnormal retinal NV does not improve and may even impair vision. The driving concept in this proposal is to create a favorable retinal environment for cell survival, vascular repair and revascularization of ischemic retina. Multiple retinal cell types participate in shaping retinal environment, including vascular endothelial cells (ECs), retinal myeloid elements/microglia/macrophages (RMCs), and neuronal elements such as retinal photoreceptor cells (PRCs) and retinal ganglion cells (RGCs). The underlying mechanisms for these cellular and molecular activities remain poorly defined. Sigma 1 Receptor (Sig1R), a unique molecular chaperone, offers a novel approach to favorably enhance the retinal environment under disease states. Activation of Sig1R provides protection against two major facets of the ischemic retina: oxidative stress and inflammation. The PI’s previous research indicated powerful retinal neuroprotection of Sig1R in retinal neurodegenerative diseases. Sig1R activation showed profound neuroprotection in retinal neurons including PRCs and RGCs. Most-recent independent research by the PI has explored the role of Sig1R in retinal vascular diseases including ROP. The PI’s preliminary data showed that: i) activation of Sig1R by its ligand (+)-pentazocine ((+)-PTZ) can markedly protect against avascularity and NV in oxygen-induced retinopathy (OIR, model of ROP); ii) (+)-PTZ administration significantly rescues impaired visual function in OIR mice; iii) (+)-PTZ treatment inhibits the release of proinflammatory and proangiogenic factors in OIR retina; iv) Sig1R knockout delays retinal vascular development at postnatal day 3. The next steps to assess this promising bi-functional (vascular and neuronal) therapeutic potential will be to characterize the novel role of Sig1R in retinal normal vascular development and vascular damage in OIR model, and further to identify which cell types/molecules are modulated/targeted by Sig1R in its reprogramming of the retinal response to ischemia in OIR. I propose to test the hypothesis that Sig1R acts as a novel key modulator of normal retinal vascular development and neurovascular damage in OIR, limits vascular injury by promoting reparative microglia/macrophages via inhibition of proinflammatory and proangiogenic factors, and provides a novel neurovascular therapy for ROP. We propose three specific aims. 1) Characterize the role of Sig1R in normal retinal vascular development and vascular damage in OIR model. 2) Test the hypothesis that Sig1R limits vascular injury by promoting reparative RMCs via inhibition of proinflammatory and proangiogenic factors. 3) Test the hypothesis that Sig1R plays a critical role in neuroprotection during ROP.