The IL-6 Induced Retinal Iron Sequestration Response

IL-6 诱导的视网膜铁螯合反应

• 批准号: 10281696
• 负责人: JOSHUA L DUNAIEF
• 金额: $ 40.6万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10281696
• 关键词: Affect; Age; Age related macular degeneration; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Alzheimer' s disease patient; Astrocytes; Bacteria; Brain; Cells; Chronic; Data; Deferoxamine; Disease; Enzyme-Linked Immunosorbent Assay; Eye; Foreign Bodies; Gene Proteins; Genotype; Goals; Growth; Hereditary Disease; Human; IL6 gene; IL6ST gene; Inductively Coupled Plasma Mass Spectrometry; Inflammation; Inherited; Injections; Interleukin-6; Iron; Iron Chelating Agents; Iron Chelation; Iron Overload; L-ferritin; Lead; Life; Messenger RNA; Modeling; Mus; Nerve Degeneration; Organ; Oxidative Stress; Paper; Parkinson Disease; Pathogenesis; Pathway interactions; Patients; Pattern; Phase II Clinical Trials; Phenotype; Proteins; Publishing; Regulation; Retina; Retinal Degeneration; Role; Signal Transduction; Stains; Systemic Therapy; TFRC gene; Techniques; Testing; Toxic effect; Transgenic Mice; Up-Regulation; Work; abeta deposition; brain cell; catalase; cell type; cytokine; extracellular; hepcidin; intraperitoneal; iron chelation therapy; metal transporting protein 1; mouse model; neuroinflammation; new therapeutic target; novel therapeutics; overexpression; oxidative damage; parent grant; pathogen; protein transport; receptor; response; retinal damage; superoxide dismutase 1; targeted treatment; uptake

PROJECT SUMMARY/ABSTRACT The goal of the proposed studies is to define an IL6 triggered cellular iron sequestration response (CISR) in a mouse model of Alzheimer's Disease (AD). Iron is necessary for growth and survival for all life forms, so cellular iron uptake and sequestration is a mechanism that limits the growth of extracellular bacteria. However, when the CISR is maladaptively activated by chronic neuroinflammation, the resulting iron accumulation can be toxic to the CNS. Toxic iron accumulation and dysregulation have been implicated in AD pathogenesis, and an ongoing phase 2 clinical trial is evaluating an iron chelator in AD patients (NCT03234686). However, understanding the mechanisms leading to iron dysregulation, and the brain cell types affected is likely to lead to a more targeted therapy than iron chelation. Evidence implicating an IL6 induced CISR in AD pathogenesis includes: 1)AD brains have iron dysregulation, with iron accumulation in plaques 2) AD brains have elevated IL6 levels near plaques. overexpressing elevated neurodegeneration Brain as in 3)A transgenic mouse IL6 i n astrocytes has brain iron accumulation. 4)The 5XFAD mouse model of AD has brain iron levels and CISR activation. 5) The iron chelator deferoxamine can ameliorate the phenotype of the AD mode l App/Ps1, another model driven by Aβ deposition. 6) iron dysregulation is also associated with Parkinson's Disease and t he hereditary diseases classified Neurodegenerations with Brain Iron Overload (NBIA). Understanding the role of the IL6 induced CISR AD pathogenesis is thus likely to lead to novel therapeutics for patients suffering from this disease.

项目摘要/摘要 拟议的研究的目的是定义IL6触发的细胞铁疗法（CISR） 在阿尔茨海默氏病小鼠模型中。铁对于所有生命形式的生长和生存都是必要的 因此，细胞铁的摄取和隔离是一种限制细胞外细菌生长的机制。 但是，当CISR因慢性神经炎症而不适适应地激活时，产生的铁 积累可能对中枢神经系统有毒。有毒铁的积累和失调已实施 在AD发病机理和正在进行的2期临床试验中，正在评估AD患者的铁螯合剂 （NCT03234686）。但是，了解导致铁失调的机制和大脑 受影响的细胞类型可能导致比铁螯合更具靶向疗法。证据隐含 AD发病机理中IL6诱导的CISR包括：1）AD大脑的铁失调，铁具有 斑块中的积累2）AD大脑在斑块附近的IL6水平升高。 过表达 高架 神经变性 脑 作为 在 3）转基因小鼠 IL6 I n星形胶质细胞具有脑铁的积累。 4）AD的5xFAD鼠标模型具有 脑铁水平和CISR激活。 5）铁螯合剂定义可以改善 广告的表型 模式L应用程序/PS1，另一个由Aβ沉积驱动的模型。 6） 铁失调也与帕金森氏病和分类的遗传性疾病有关 脑铁超负荷（NBIA）的神经退行性。 了解IL6诱导CISR的作用 因此，AD发病机理可能会为患有这种疾病的患者提供新的治疗。