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.
发作性睡病合并猝倒(N/C)是一种常见的睡眠障碍,但对其潜在原因了解甚少 导致N/C的机制,以及为什么一些患者症状严重,而另一些患者症状不严重。导致N/C 通过选择性地丧失产生食欲素神经肽的下丘脑神经元,并与 具有主要组织相容性复合体(MHC)II类等位基因DQB1*0602。我们假设N/C是 由CD4+或CD8+T细胞对产生增食欲素的下丘脑神经元的反应引起 神经肽,更具侵袭性的免疫反应导致N/C严重程度增加。 这一假说得到了一些出版物的支持,这些出版物表明细胞免疫反应具有因果关系。 以及我们自己的初步数据。我们的长期目标是了解N/C的原因和 疾病严重程度的决定因素。在这样做的同时,我们还将为早期患者设计一种亟需的血液测试 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 启动对增食欲素肽的细胞免疫反应,以及这种反应是否与更多 严重的症状。理由是这些拟议的研究将使我们能够开发出一种早期的血液测试 N/C的诊断和疾病严重程度的预测。 为了验证这些假设,我们将追求以下一套具体目标: 目的1)DQB1的疾病严重程度与增食欲素神经肽的细胞免疫应答相关 *0602+发作性睡病患者。我们将使用Well-来测量嗜睡症症状的严重程度- 验证量表和症状严重程度与CD4+或CD8+T细胞对食欲素肽的反应性相关 使用三种不同的检测方法:1)细胞内细胞因子染色(ICS)检测2)细胞上Luminex xMAP微珠阵列 培养上清液;3)RT-qPCR检测细胞RNA上的细胞因子mRNA。 目的2)确定DQB1*0602+中CD4+或CD8+T细胞识别的免疫优势增食欲素表位 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,并设计一种 诊断血液测试和N/C疾病严重程度的预测因子 这种方法是创新的,因为它通过专注于细胞 导致N/C的机制这项拟议的研究具有重要意义,因为它将使我们能够确定 导致N/C的免疫病理机制,开发一种用于N/C早期诊断和预测的血液检测方法 疾病的严重性。从这些研究中获得的知识也将对 推进睡眠障碍和神经免疫学领域。

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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