Reversing the ocular impact of NM and SM through novel therapies

通过新疗法扭转 NM 和 SM 对眼部的影响

• 批准号: 10490420
• 负责人: ROBERT M LAVKER
• 金额: $ 49.33万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-17 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10490420
• 关键词: Acute; Adverse effects; Affect; Aftercare; Anterior; Anti-Inflammatory Agents; Attenuated; Autophagocytosis; Binding; Biological; Cells; Characteristics; Chemical Burns; Chemical Warfare Agents; Cholecalciferol; Clinical; Collagen; Complex; Cornea; Corneal Injury; Corneal Neovascularization; Data; Defect; Deterioration; Development; Dyes; Epithelial; Evaluation; Exclusion; Exposure to; Eye; Eye Injuries; Eyedrops; Film; Fluorescein; Funding; Glycolates; High Density Lipoproteins; Immune; Immunologics; Inflammation; Inflammatory; Injury; Ischemia; Knowledge; Laboratories; Light; Lipids; Mechlorethamine; MicroRNAs; Modality; Morphology; Mus; Mustard Gas; Non-Steroidal Anti-Inflammatory Agents; Oryctolagus cuniculus; Patients; Penetration; Peripheral; Phase; Phenotype; Protocols documentation; Regimen; Signal Transduction; Stains; Steroids; Stress; Surface; System; Testing; Therapeutic; Thinness; Tissues; Topical application; Universities; Variant; Vision; acute symptom; analog; angiogenesis; base; corneal epithelium; cytokine; delivery vehicle; efficacy evaluation; healing; improved; inflammatory marker; innovation; limbal; nano; nanoparticle; neovascularization; novel; novel therapeutics; ocular surface; particle; patient subsets; preservation; prevent; response; scaffold; screening program; side effect; stem cells; translational potential; wound healing

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.

项目摘要/摘要 眼前表面与泪膜结合提供了防御渗透的第一道防线 有害代理人，可能会对视力产生不利影响。一旦这个两个组件系统被破坏， 前表面能够安装剧烈的反应，这涉及相对较快的重新响应 上皮化以及轻快的发作发作。前部对响应的变体 暴露于化学战剂硫芥末（SM）后，患者发生了扰动。这 急性症状通常在2-6周后完全消除而不会进一步炎症。但是，在子集中 患者，角膜上皮侵蚀，边缘性缺血以及偶尔的外周角膜稀疏和 新血管形成可能会缓慢发展。关于治疗方式，无论是类固醇还是非甾体类固醇 抗炎药是急性和延长相的公认治疗方法。但是，长期 在SM眼部损伤中使用局部类固醇不是理想的。因此，防止眼的其他疗法 SM受害者的恶化是一个主要的未满足需求。我们最近证明了局部应用 合成的，功能性高密度脂蛋白纳米颗粒（HDL NP）固有增强的重新上皮化 角膜伤后，可以在角膜燃烧后充当抗炎剂。 此外，HDL NP是将miRNA传递到角膜的有效车辆。因此，HDL NP 将与角膜中高度血管静脉miRNA miR-184复合，以治疗NM-的延迟相 诱发角膜损伤。我们还有证据表明维生素D3（VIT D3）和聚（乳酸 - 糖酸）免疫 从系统地修改纳米颗粒（PLGA-IMP）或局部进行HDL NP 暴露于局部氮芥末（NM），SM的类似物，显着降低了促炎和 血管生成信号传导。总的来说，这些关于HDL，VIT D3，MIR-184和PLGA-IMP的观察结果很广 翻译潜力是SM诱导眼睛损伤的新型治疗方式。为了测试这个想法，我们将 开发和评估这些局部眼疗法，以针对小鼠NM损伤的急性和延迟阶段。 我们将通过临床，结合这些处理来评估这些处理的疗效和机制 形态学，细胞生物学和免疫学方法。此外，我们将评估新的HDL类 用有机的，透明的脂质偶联的核心支架代替无机AU核的NP 不抑制光的通过。我们还将评估系统给药VIT D3或PLGA-的实用性 小动物可以治疗NM诱导的眼部损伤的延迟期。这些结果将建立最有效的 局部和全身性方案，以治疗NM损伤的急性和延迟阶段。最后，我们将应用此 知识以评估我们所选治疗方法使用这些方法在兔子眼中SM损伤的功效 描述了NM损伤。最终，我们的研究将为SM诱导的伤害产生创新的治疗方法 具有抗炎，抗血管生成，促进性的，能力最小的副作用。