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

项目摘要 早产儿视网膜病（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停滞。视网膜无血供和随之而来的缺氧 导致增殖性致盲性新血管形成（NV）。缺血诱导视网膜细胞功能障碍， 不可逆的细胞损伤NV治疗视力下降。然而，目前的临床护理标准 靶向异常视网膜NV不会改善甚至可能损害视力。这辆车的驾驶理念 一项建议是为细胞存活、血管修复和血管重建创造一个有利的视网膜环境 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）、视网膜髓样细胞/小胶质细胞/巨噬细胞（RMCs）和神经元细胞 如视网膜感光细胞（PRCs）和视网膜神经节细胞（RGC）。潜在的机制 对于这些细胞和分子的活动仍然很难定义。Sigma 1受体（Sig 1 R），一种独特的 分子伴侣，提供了一种新的方法，有利地提高视网膜环境下的疾病 states. Sig 1 R的激活提供了对缺血性视网膜的两个主要方面的保护：氧化性视网膜损伤。 压力和炎症。PI先前的研究表明，Sig 1 R对视网膜神经细胞具有强大的保护作用， 视网膜神经变性疾病Sig 1 R激活显示了对视网膜神经元的深刻神经保护作用 包括PRC和RGC。PI最近的独立研究探讨了Sig 1 R在以下方面的作用： 视网膜血管疾病，包括ROP。PI的初步数据显示：i）Sig 1 R的激活， 配体（+）-喷他佐辛（（+）-PTZ）可显著对抗氧诱导的血管缺血和NV 视网膜病变（OIR，ROP模型）; ii）（+）-PTZ给药显著挽救了视网膜病变中受损的视觉功能。 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）Sig 1 R敲除延迟出生后第3天的视网膜血管发育。下一步评估 这种有希望的双功能（血管和神经元）治疗潜力将表征新的 Sig 1 R在OIR模型中视网膜正常血管发育和血管损伤中的作用，并进一步 识别哪些细胞类型/分子在视网膜的重编程中被Sig 1 R调节/靶向 我建议测试的假设，Sig 1 R作为一种新的关键调制器， OIR中正常的视网膜血管发育和神经血管损伤，通过促进 通过抑制促炎因子和促血管生成因子来修复小胶质细胞/巨噬细胞，并提供 一种治疗ROP的新的神经血管疗法。我们提出三个具体目标。1)描述Sig 1 R的作用 在正常视网膜血管发育和OIR模型中的血管损伤中。2)测试的假设 Sig 1 R通过抑制促炎性细胞因子和血管内皮细胞因子来促进修复性RMC，从而限制血管损伤。 促血管生成因子3)检验Sig 1 R在ROP期间的神经保护中起关键作用的假设。

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.