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.

项目总结/摘要 所提出的研究的目标是定义IL 6触发的细胞铁螯合反应（CISR）。 在阿尔茨海默病（AD）的小鼠模型中。铁是所有生命形式生长和生存所必需的， 所以细胞铁的摄取和螯合是限制细胞外细菌生长的机制。 然而，当CISR被慢性神经炎症不适应地激活时， 蓄积可能对CNS有毒。有毒的铁积累和失调已经牵连 正在进行的2期临床试验正在评估铁螯合剂在AD患者中的作用 （NCT03234686）。然而，了解导致铁失调的机制， 受影响的细胞类型可能导致比铁螯合更有针对性的治疗。的证据涉及 IL 6诱导的CISR在AD发病机制中包括：1）AD脑具有铁失调， 2）AD脑在斑块附近具有升高的IL 6水平。 过表达 升高 神经变性 大脑 作为 在 3）转基因小鼠 星形胶质细胞中的IL 6具有脑铁蓄积作用。4)AD的5XFAD小鼠模型具有 脑铁水平和CISR激活。5)铁螯合剂去铁胺能改善 AD表型 模式l App/Ps1，另一个由Aβ沉积驱动的模式。六、 铁失调也与帕金森病和遗传性疾病有关， 脑铁超载（NBIA） 了解IL 6诱导的CISR的作用 因此，AD发病机制可能导致患有这种疾病的患者的新疗法。