Reversing the ocular impact of NM and SM through novel therapies

项目总结/摘要 眼前表面与泪膜一起提供了防止穿透的第一道防线 有害物质，会对视力产生不利影响。一旦这两个组成部分的系统被破坏， 前表面能够安装一个有力的反应，这涉及一个相对快速的重新， 上皮形成沿着活跃的炎症发作。眼前节对以下刺激的反应的一种变体 在暴露于化学战剂硫芥子气（SM）之后，患者会发生扰动。的 急性症状通常在2-6周后完全消退而没有进一步的炎症。然而，在一个子集中， 患者的角膜上皮糜烂、角膜缘缺血，偶尔出现周边角膜变薄， 新血管形成可能缓慢进展。关于治疗方式，类固醇或非类固醇 抗炎药是急性期和长期期的公认治疗方法。但长期 在SM眼损伤中使用局部类固醇并不理想。因此，预防眼部疾病的其他疗法 性虐待受害者的病情恶化是一个未得到满足的主要需求。我们最近证明，局部应用 合成的功能性高密度脂蛋白纳米颗粒（HDL NPs）固有地增强上皮再生 并且可以在角膜化学烧伤后充当抗炎剂。 此外，HDL NP是将miRNA递送至角膜的有效载体。因此，HDL NP 将与miR-184复合，miR-184是角膜中一种高度抑制血管生成的miRNA，用于治疗NM-1的延迟期。 导致角膜损伤。我们也有证据表明，维生素D3（维生素D3）和聚（乳酸-羟基乙酸）免疫 修饰的纳米颗粒（PLGA-IMP）或局部施用HDL NP， 暴露于局部氮芥（NM），SM的类似物，显着降低促炎和 血管生成信号总的来说，这些对HDL、Vit D3、miR-184和PLGA-IMP的观察结果具有巨大的意义。 翻译潜力作为SM诱导的眼损伤的新型治疗方式。为了验证这个想法，我们将 开发和评估这些局部眼部治疗剂用于小鼠NM损伤的急性期和延迟期。 我们将结合临床， 形态学、细胞生物学和免疫学方法。此外，我们还将评估一类新的HDL 用有机透明脂质缀合的核心支架替代无机Au核心的NP，其将 不阻碍光的通过。我们还将评估全身给予维生素D3或PLGA的效用， IMP治疗NM诱导的眼损伤的延迟期。这些结果将建立最有效的 局部和全身方案治疗NM损伤的急性期和延迟期。最后，我们将应用此 知识，以评估我们选择的治疗方法对兔眼SM损伤的有效性， 描述为NM损伤。最终，我们的研究将为SM诱导的损伤提供创新的治疗方法， 具有抗炎、抗血管生成、促进消退的能力，副作用最小。

PROJECT SUMMARY/ABSTRACT The ocular anterior surface in conjunction with the tear film provide the first line of defense against penetration of noxious agents, which can adversely affect vision. Once this two-component system is breached, the anterior surface is capable of mounting a vigorous response, which involves a relatively rapid re- epithelialization along with a brisk inflammatory episode. A variant on the response of the anterior segment to perturbation occurs to patients following exposure to the chemical warfare agent, sulfur mustard (SM). The acute symptoms usually resolve completely without further inflammation after 2-6 weeks. However, in a subset of patients, corneal epithelial erosions, limbal ischemia, and, occasionally, peripheral corneal thinning and neovascularization may slowly progress. With respect to treatment modalities, either steroidal or non-steroidal anti-inflammatory drugs are the accepted treatment for the acute and prolonged phases. However, long-term use of topical steroids in SM ocular injuries is not ideal. Thus, additional therapies to prevent the ocular deterioration of SM victims is a major unmet need. We have recently demonstrated that topical application of synthetic, functional high-density lipoprotein nanoparticles (HDL NPs) inherently enhance re-epithelialization following corneal wounding and can act as anti-inflammatory agents following a chemical burn to the cornea. Furthermore, HDL NPs are effective vehicles for the delivery of miRNAs to the cornea. Therefore, HDL NPs will be complexed with miR-184, a highly angiostatic miRNA in the cornea, to treat the delayed phase of NM- induced corneal injury. We also have evidence that Vitamin D3 (Vit D3) and poly(lactic-co-glycolicacid) immune modifying nanoparticles (PLGA-IMPs) systemically or HDL NPs topically, administered to mice that were exposed to topical nitrogen mustard (NM), an analogue of SM, significantly reduce pro-inflammatory and angiogenic signaling. Collectively, these observations on HDLs, Vit D3, miR-184 and PLGA-IMPs have vast translational potential as novel treatment modalities for SM-induced injury to the eye. To test this idea, we will develop and assess these topical ocular therapeutics for the acute and delayed phases of NM injury to mice. We will evaluate the efficacy and mechanisms underlying these treatments with a combination of clinical, morphological, cell biological and immunological approaches. Additionally, we will evaluate a new class of HDL NPs that replace the inorganic Au core with an organic, transparent lipid-conjugated core scaffold, which will not inhibit the passage of light. We will also appraise the utility of systemic administration of Vit D3 or PLGA- IMPs to treat the delayed phase of NM-induced ocular injury. These results will establish the most effective topical and systemic regimens to treat the acute and delayed phases of NM injury. Finally, we will apply this knowledge to evaluate the efficacy of our chosen treatments for SM injury in rabbit eyes using the approaches described for NM injury. Ultimately, our studies will yield innovative treatments for SM-induced injury that will have anti-inflammatory, anti-angiogenic, pro-resolving, capabilities with minimal side effects.