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

项目概要 早产儿视网膜病变（ROP）是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。视网膜无血管和随之而来的缺氧 导致增殖性致盲性新生血管形成（NV）。缺血会导致视网膜细胞功能障碍 不可逆的细胞损伤。 NV 会加剧视力恶化。然而，目前的临床护理标准 针对异常视网膜 NV 并不能改善视力，甚至可能损害视力。这其中的驾驶理念 提议是为细胞存活、血管修复和血运重建创造有利的视网膜环境 缺血性视网膜。多种视网膜细胞类型参与塑造视网膜环境，包括血管 内皮细胞 (EC)、视网膜髓样成分/小胶质细胞/巨噬细胞 (RMC) 和神经元成分 例如视网膜感光细胞（PRC）和视网膜神经节细胞（RGC）。底层机制 因为这些细胞和分子活动仍然不明确。 Sigma 1 受体 (Sig1R)，一种独特的 分子伴侣，提供了一种有利于增强疾病下视网膜环境的新方法 州。 Sig1R 的激活可针对缺血性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 对视网膜神经具有强大的保护作用 视网膜神经退行性疾病。 Sig1R 激活对视网膜神经元具有深远的神经保护作用 包括中华人民共和国和研究资助机构。 PI 最近的独立研究探讨了 Sig1R 在 视网膜血管疾病，包括 ROP。 PI 的初步数据表明： i) Sig1R 的激活 配体 ( )-喷他佐辛 (( )-PTZ) 可显着预防氧诱导的无血管和 NV 视网膜病变（OIR，ROP 模型）； ii) ( )-PTZ 管理可显着挽救受损的视功能 OIR 小鼠； iii) ( )-PTZ 治疗抑制 OIR 中促炎和促血管生成因子的释放 视网膜； iv) Sig1R 敲除延迟出生后第 3 天的视网膜血管发育。接下来的评估步骤 这种有前途的双功能（血管和神经元）治疗潜力将成为新型药物的特征 OIR模型中Sig1R在视网膜正常血管发育和血管损伤中的作用，并进一步 确定 Sig1R 在视网膜重编程中调节/靶向哪些细胞类型/分子 对 OIR 缺血的反应。我建议检验 Sig1R 作为新型关键调制器的假设 OIR 中正常的视网膜血管发育和神经血管损伤，通过促进 通过抑制促炎和促血管生成因子来修复小胶质细胞/巨噬细胞，并提供 一种针对 ROP 的新型神经血管疗法。我们提出三个具体目标。 1) 表征Sig1R的作用 OIR 模型中正常视网膜血管发育和血管损伤。 2）检验假设 Sig1R 通过抑制促炎和促进 RMC 修复来限制血管损伤 促血管生成因子。 3) 检验 Sig1R 在 ROP 期间的神经保护中发挥关键作用的假设。

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.