Cellular auto-immune mechanisms of narcolepsy

发作性睡病的细胞自身免疫机制

基本信息

  • 批准号:
    9335997
  • 负责人:
  • 金额:
    $ 20.42万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2016
  • 资助国家:
    美国
  • 起止时间:
    2016-09-01 至 2019-08-31
  • 项目状态:
    已结题

项目摘要

Narcolepsy with Cataplexy (N/C) is a common sleep disorder, but very little is understood about the underlying mechanism that causes N/C and why symptoms are severe in some patients but not in others. N/C is caused by selective loss of the hypothalamic neurons that produce the orexin neuropeptides and is strongly associated with the Major Histocompatibility Complex (MHC) class II allele DQB1 *0602. We hypothesize that N/C is caused by CD4+ or CD8+ T cells response directed against the hypothalamic neurons producing the orexin neuropeptides, and that a more aggressive immune response results in increased severity of N/C. This hypothesis is supported by a number of publications suggesting a causal role of the cellular immune response in N/C as well as our own preliminary data. Our long term goal is to understand the cause of N/C and the determinants of disease severity. In doing so, we will also devise a much needed blood test for the early diagnosis of NC and prediction of disease severity. Our objectives are to determine whether N/C patients mount a cellular immune response to orexin peptides and whether this response is associated with more severe symptoms. The rationale is that these proposed studies will enable us to develop a blood test for early diagnosis of N/C and predictor of disease severity. To test these hypotheses, we will pursue the following set of Specific Aims: Aim 1) Correlate disease severity with the cellular immune response to orexin neuropeptides in DQB1 *0602+ Narcolepsy with Cataplexy patients. We will measure narcolepsy symptoms severity using well- validated scales and correlate symptom severity with the reactivity of CD4+ or CD8+ T cells to orexin peptides using three different assays: 1) Intracellular Cytokine Staining (ICS) assay 2) Luminex xMAP bead array on cell culture supernatant and 3) RT-qPCR for cytokine mRNA on cellular RNA . Aim 2) Identify immunodominant orexin epitopes recognized by CD4+ or CD8+ T cells in DQB1 *0602+ Narcolepsy with Cataplexy patients. We will map orexin epitopes in N/C patients using ICS and devise a diagnostic blood test and predictor of disease severity for N/C. The approach is innovative, because it departs significantly from the status quo by focusing on the cellular mechanisms leading to N/C. The proposed research is significant because it will allow us to identify the immunopathogenic mechanisms leading to N/C, develop a blood test for early diagnosis of N/C and predict disease severity. The knowledge gained from these studies will also have far reaching implications in advancing the fields of Sleep Disorders and Neuro-Immunology.
发作性睡病伴猝倒 (N/C) 是一种常见的睡眠障碍,但对其潜在的原因知之甚少 导致 N/C 的机制以及为什么某些患者的症状较严重而其他患者则不然。 N/C 引起 通过选择性丧失产生食欲素神经肽并与之密切相关的下丘脑神经元 具有主要组织相容性复合物 (MHC) II 类等位基因 DQB1 *0602。我们假设 N/C 是 由 CD4+ 或 CD8+ T 细胞针对产生食欲素的下丘脑神经元的反应引起 神经肽,更积极的免疫反应会导致 N/C 严重程度增加。这 该假设得到了许多出版物的支持,表明细胞免疫反应的因果作用 N/C 以及我们自己的初步数据。我们的长期目标是了解 N/C 的原因以及 疾病严重程度的决定因素。在此过程中,我们还将为早期患者设计急需的血液测试。 NC 的诊断和疾病严重程度的预测。我们的目标是确定 N/C 患者是否 对食欲素肽产生细胞免疫反应,以及这种反应是否与更多相关 严重的症状。理由是,这些拟议的研究将使我们能够开发一种血液测试来早期诊断 N/C 的诊断和疾病严重程度的预测。 为了检验这些假设,我们将追求以下一组具体目标: 目标 1) 将疾病严重程度与 DQB1 中食欲素神经肽的细胞免疫反应相关联 *0602+ 猝倒患者发作性睡病。我们将使用良好的方法来测量发作性睡病症状的严重程度 经过验证的量表并将症状严重程度与 CD4+ 或 CD8+ T 细胞对食欲素肽的反应性相关联 使用三种不同的测定:1) 细胞内细胞因子染色 (ICS) 测定 2) 细胞上的 Luminex xMAP 珠阵列 培养上清液和 3) RT-qPCR 检测细胞 RNA 上的细胞因子 mRNA。 目标 2) 鉴定 DQB1 *0602+ 中 CD4+ 或 CD8+ T 细胞识别的免疫显性食欲素表位 发作性睡病与猝倒患者。我们将使用 ICS 绘制 N/C 患者的食欲素表位图并设计一个 N/C 的诊断性血液检测和疾病严重程度的预测。 该方法是创新的,因为它通过专注于蜂窝技术而显着偏离现状。 导致 N/C 的机制。拟议的研究意义重大,因为它将使我们能够确定 导致 N/C 的免疫致病机制,开发血液检测以早期诊断 N/C 并预测 疾病的严重程度。从这些研究中获得的知识也将产生深远的影响 推进睡眠障碍和神经免疫学领域的发展。

项目成果

期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

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Igor J Koralnik其他文献

Igor J Koralnik的其他文献

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{{ truncateString('Igor J Koralnik', 18)}}的其他基金

Contribution of the Virome to Alzheimer's pathogenesis
病毒组对阿尔茨海默病发病机制的贡献
  • 批准号:
    10287010
  • 财政年份:
    2020
  • 资助金额:
    $ 20.42万
  • 项目类别:
Contribution of the Virome to HIV/AIDS pathogenesis
病毒组对艾滋病毒/艾滋病发病机制的贡献
  • 批准号:
    10407597
  • 财政年份:
    2020
  • 资助金额:
    $ 20.42万
  • 项目类别:
Contribution of the Virome to HIV/AIDS pathogenesis
病毒组对艾滋病毒/艾滋病发病机制的贡献
  • 批准号:
    9975173
  • 财政年份:
    2020
  • 资助金额:
    $ 20.42万
  • 项目类别:
Contribution of the Virome to HIV/AIDS pathogenesis
病毒组对艾滋病毒/艾滋病发病机制的贡献
  • 批准号:
    10076416
  • 财政年份:
    2020
  • 资助金额:
    $ 20.42万
  • 项目类别:
Contribution of the Virome to HIV/AIDS pathogenesis
病毒组对艾滋病毒/艾滋病发病机制的贡献
  • 批准号:
    10159233
  • 财政年份:
    2020
  • 资助金额:
    $ 20.42万
  • 项目类别:
Role of Inflammation in Progressive Multifocal Leukoencephalopathy
炎症在进行性多灶性白质脑病中的作用
  • 批准号:
    9334313
  • 财政年份:
    2017
  • 资助金额:
    $ 20.42万
  • 项目类别:
Cellular auto-immune mechanisms of narcolepsy
发作性睡病的细胞自身免疫机制
  • 批准号:
    9404243
  • 财政年份:
    2016
  • 资助金额:
    $ 20.42万
  • 项目类别:
Pathogenesis of a JC Virus Variant in Pyramidal Neurons
JC 病毒变异体在锥体神经元中的发病机制
  • 批准号:
    8788562
  • 财政年份:
    2012
  • 资助金额:
    $ 20.42万
  • 项目类别:
Pathogenesis of a JC Virus Variant in Pyramidal Neurons
JC 病毒变异体在锥体神经元中的发病机制
  • 批准号:
    8420424
  • 财政年份:
    2012
  • 资助金额:
    $ 20.42万
  • 项目类别:
Pathogenesis of a JC Virus Variant in Pyramidal Neurons
JC 病毒变异体在锥体神经元中的发病机制
  • 批准号:
    8289758
  • 财政年份:
    2012
  • 资助金额:
    $ 20.42万
  • 项目类别:

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