The IL-6 Induced Retinal Iron Sequestration Response

项目摘要/摘要 拟议研究的目标是定义IL6触发的细胞铁封存反应(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， 因此，细胞对铁的吸收和隔离是限制细胞外细菌生长的一种机制。 然而，当慢性神经炎导致CISR不适应地激活时，产生的铁 蓄积对中枢神经系统可能是有害的。有毒的铁蓄积和失调已被牵连。 在AD发病机制中，一项正在进行的第二阶段临床试验正在评估一种铁络合剂在AD患者中的作用 (NCT03234686)。然而，了解导致铁调节失调的机制，以及大脑 受影响的细胞类型可能会导致比铁络合更有针对性的治疗。牵连的证据 在阿尔茨海默病的发病机制中，IL6诱导的CISR包括：1)阿尔茨海默病脑内有铁的失调，与铁 斑块中的积聚2)阿尔茨海默病患者大脑中斑块附近的IL6水平升高。 过度表达 高架 神经退行性变 脑区 AS 在……里面 3)转基因小鼠 星形胶质细胞存在脑内铁蓄积。4)AD的5XFAD小鼠模型 脑铁水平和CISR激活。5)铁络合剂去铁胺可改善 AD的表型 模式L应用程序/PS1，另一种模式由Aβ沉积驱动。6) 铁代谢失调也与帕金森氏症和遗传性疾病有关 脑铁超载的神经退行性变(NBIA)。 了解IL6诱导的CISR的作用 因此，AD的发病机制可能导致对患有这种疾病的患者进行新的治疗。

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.