The role of iron in retinal degeneration during bacterial infection

铁在细菌感染期间视网膜变性中的作用

• 批准号: 10676039
• 负责人: Sierra Foshe
• 金额: $ 4.77万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2027-02-19
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10676039
• 关键词: Acute; Animal Model; Anti-Bacterial Agents; Anti-Inflammatory Agents; Antibiotic Resistance; Antibiotics; Bacteria; Bacterial Infections; Binding; Blindness; Cell Proliferation; Cell Survival; Cells; Central Nervous System Infections; Clinical; Colony-forming units; Complication; Data; Disease; Dose; Drug Kinetics; Endophthalmitis; Excision; Eye; Genes; Goals; Growth; Histology; Hour; Image; Immune; In Situ; In Vitro; Infection; Inflammation; Inflammatory; Inflammatory Response; Injections; Injury; Invaded; Iron; Iron Chelating Agents; Iron Chelation; Iron Overload; Lead; Left; Leukocytes; Link; Liquid substance; Macrophage; Mass Spectrum Analysis; Microglia; Modeling; Mus; Natural regeneration; Neurons; Operative Surgical Procedures; Oxidative Stress; Patient-Focused Outcomes; Patients; Predisposition; Proliferating; Regulation; Regulator Genes; Retina; Retinal Degeneration; Retinal Detachment; Retinal Diseases; Role; Saline; Sorting; Stains; Staphylococcus aureus; Staphylococcus aureus infection; Sterility; Structure; Surgical complication; Symptoms; Testing; Time; Tissues; Virulence; Visualization; Wild Type Mouse; bacterial endophthalmitis; cohort; cytokine; effectiveness evaluation; immune activation; improved; in vivo; mouse model; neurotoxic; operation; pathogenic bacteria; preservation; prevent; pyridine; response; translational applications; uptake

PROJECT SUMMARY When bacteria invade the eye, the resulting damage is rapid and irreversible. This type of infection, called endophthalmitis, is the most severe complication of intraocular surgery. Patient outcome is heavily dependent on the pathogenicity of the bacteria, its susceptibility to antibiotics, and the extent of inflammation. These factors can influence progression to the worst-case scenario, where the infected eye must be completely removed. Even in milder cases, some amount of permanent vision loss is common. Therefore, there is need for a treatment which targets both contributors to vision loss: bacterial growth and neurotoxic inflammation. All bacteria require iron for survival and proliferation. During infection, they must obtain iron from host tissues. In response, host cells will import iron to shield it from bacteria, initiating a competition for iron acquisition. However, iron accumulation within immune cells can promote inflammation. In animal models of diverse infections and diseases, iron chelation is both anti-bacterial and anti-inflammatory. My preliminary ex vivo data suggests that iron chelation inhibits bacterial growth in vitreous (fluid from within the eye), and that acute iron chelation is nontoxic to the retina. Aim 1 will expand on these results to determine the effectiveness of an iron chelator at preventing endophthalmitis in mice. I will examine the extent to which bacterial growth is inhibited and retinal structure is preserved over time. Although reducing bacteria would naturally reduce inflammation, the direct anti-inflammatory contribution of iron chelation would be unclear. Therefore, Aim 2 will investigate the link between iron accumulation and retinal inflammation. Using the murine endophthalmitis model, I will examine iron levels within retinal macrophages/microglia, and to what extent an iron chelator reduces retinal inflammation. The result will determine the anti-inflammatory potential of iron chelation treatment for endophthalmitis. The overall goal of this proposal is to prevent vision loss caused by bacterial infection.

项目摘要 当细菌侵入眼睛时，造成的损害是迅速和不可逆转的。这种类型的感染，称为 眼内炎是眼内手术最严重的并发症。患者结局严重依赖于 细菌的致病性、对抗生素的敏感性以及炎症的程度。这些 这些因素可能会影响进展到最坏的情况，在这种情况下，受感染的眼睛必须完全 删除.即使在较轻的情况下，一些永久性视力丧失也是常见的。因此，有必要 针对导致视力丧失的两个因素：细菌生长和神经毒性炎症。所有 细菌需要铁来生存和增殖。在感染期间，它们必须从宿主组织中获得铁。在 作为反应，宿主细胞将输入铁以保护其免受细菌的侵害，从而引发对铁获取的竞争。 然而，免疫细胞内的铁积累会促进炎症。在各种动物模型中， 对于感染和疾病，铁螯合物既抗菌又抗炎。我初步的体外实验 数据表明铁螯合抑制玻璃体（眼内液体）中的细菌生长， 铁螯合对视网膜是无毒的。目标1将扩展这些结果，以确定 铁螯合剂预防小鼠眼内炎的实验研究我会检查细菌生长的程度 抑制和视网膜结构随时间保存。虽然还原细菌会自然地减少 在炎症中，铁螯合的直接抗炎作用尚不清楚。因此，目标2将 研究铁积累和视网膜炎症之间的联系。利用小鼠眼内炎 模型，我将检查视网膜巨噬细胞/小胶质细胞内的铁水平，以及铁螯合剂在多大程度上 减少视网膜炎症。结果将确定铁螯合的抗炎潜力 治疗眼内炎。这项建议的总体目标是防止细菌性失明， 感染