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The Role of Ionizing Radiation in Alzheimer’s Disease

The Role of Ionizing Radiation in Alzheimer’s Disease
电离辐射在阿尔茨海默病中的作用
批准号:
10288222
负责人:
Max Brenner
金额:
$41.88万
依托单位国家:
美国
项目类别:
财政年份:
2017
资助国家:
美国
项目状态:
已结题
起止时间:
2017-06-07 至 2022-05-31

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中文摘要
翻译
项目描述:本行政补充项目的目标是确定是否
英文摘要
PROJECT DESCRIPTION: The goal of this Administrative Supplement project is to determine whether extracellular cold inducible RNA-binding protein (eCIRP), a damage-associated molecular pattern (DAMP) molecule, is released by microglial cells upon radiation exposure and leads to tau pathology in Alzheimer’s disease (AD). AD is the 6th leading cause of death in the US and the most common form of neurodegenerative dementia. Although studies have linked ionizing radiation exposure to cognitive dysfunction, the role of radiation injury in the etiology of AD has not been sufficiently explored. eCIRP is known to be released by irradiated cells and activated macrophages, and our preliminary studies have shown that serum levels of eCIRP are elevated after total body irradiation (TBI), raising the possibility that TBI may cause microglial cells to release eCIRP in the central nervous system. Indeed, we discovered that eCIRP was increased in the cerebrospinal fluid of AD patients. Moreover, eCIRP increased tau phosphorylation and upregulated the Cdk5 hyperactivator p25 via eCIRP’s activation of the interleukin-6 receptor α (IL-6Rα)/STAT3 pathway. We also showed that the eCIRP competitive antagonist small peptide C23 inhibited eCIRP’s activation of IL-6Rα/STAT3 and upregulation of p25. Based on these novel findings, we hypothesize that ionizing radiation induces microglial cells to release eCIRP in the brain, leading to pathological tau phosphorylation and aggregation. Moreover, we further hypothesize that treatment with C23 attenuates the development of radiation-induced tau pathology. In this project, we plan to determine the effects of irradiation and the contribution of microglial cells to brain eCIRP release. We will then demonstrate the role of eCIRP in the induction of AD-like pathological tau phosphorylation and aggregation after irradiation. Finally, we will conduct a proof-of-concept study to evaluate whether eCIRP antagonism with C23 attenuates pathological tau phosphorylation and aggregation after TBI. Our studies will provide novel pivotal insights into the precise role of ionizing radiation in the pathogenesis of AD, as well as new potential therapeutic strategies for treating AD patients in the future.
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eCIRP-Neutralizing mAb for Acute Lung Injury in Sepsis
  • 批准号:
    10632117
  • 项目类别:
  • 资助金额:
    $12.98万
  • 财政年份:
    2022
  • 负责人:
    Max Brenner
  • 依托单位:
Mechanisms of Radiation-induced Vascular Endothelial Cell Injury and Its Correction
Mechanisms of Radiation-induced Vascular Endothelial Cell Injury and Its Correction
Mechanisms of Radiation-induced Vascular Endothelial Cell Injury and Its Correction
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