Astrocytic control of lymphocyte migration and differentiation in CNS inflammatory lesions

星形胶质细胞控制中枢神经系统炎症病变中淋巴细胞迁移和分化

基本信息

  • 批准号:
    10228699
  • 负责人:
  • 金额:
    $ 19.33万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2018
  • 资助国家:
    美国
  • 起止时间:
    2018-09-01 至 2023-08-31
  • 项目状态:
    已结题

项目摘要

Clinical disability in multiple sclerosis (MS) is driven by immune cell infiltration into the CNS parenchyma. Understanding the mechanisms by which CNS barrier cells regulate immune cell activation and entry during this infiltrative process may identify translational strategies against MS and other autoimmune CNS diseases. During CNS inflammation, immune cells traffic from the blood through a two-barrier structure termed the neurovascular unit. While many have focused on entry through the first barrier, a specialized endothelial wall known as the blood-brain barrier, less is known about how immune cells interact with the second barrier, a layer of astrocyte end feet termed the glia limitans. In MS lesions, immune cells circulate in the space between the blood-brain barrier and the glia limitans, a compartment called the perivascular space. Here, astrocytes may interact with infiltrating immune cells to regulate their function. Using gene expression analysis, we identified immune cell receptors upregulated by astrocytes when treated with interleukin-1β, a cytokine in MS lesions. One of our strongest candidates, Junctional Adhesion Molecule-A (JAM-A), is an immune cell receptor that regulates pro-inflammatory pathways in other tissues. My pilot data reveals that astrocytic JAM-A Binds T cells and alters protease and cytokine levels in patterns known to exacerbate an animal model of MS. Further pilot data show that astrocytic JAM-A deletion blocks immune cell penetration of the glia limitans and protects against clinical disability in this model. I hypothesize that astrocytic JAM-A drives CNS entry of immune cells, inflammatory lesion formation and clinical disability. In Aim 1, I will test how astrocytic JAM-A signaling to T cells in co-culture modifies gene expression networks of both cell types using RNA sequencing, and then I will determine how JAM-A and downstream candidates regulate effector pathways relevant to autoimmune attack. In Aim 2, using transgenic and pharmacologic tools, I will establish how astrocytic JAM-A controls lesion formation in two animal models of CNS inflammation. Translational strategies blocking astrocytic JAM-A and effectors will then be tested against clinical disability in an animal model of MS. In Aim 3, I will measure how T cells interact with the glia limitans using live two-photon imaging of inflammatory spinal cord lesions. I will then test how astrocytic JAM-A and effectors regulate these interactions. Goals of this K08 award are to advance my expertise in neuroimmunology and glial biology under the mentorships of Gareth John, PhD., Peter Calabresi, MD. and Dimitrios Davalos, PhD., to acquire technical skills using immune and glial cell co-cultures and in vivo multiphoton imaging, and to establish my own research group focused on the role of astrocyte-immune cell signaling during autoimmune attack. This K08 plan investigates a novel contact-mediated interaction between reactive astrocytes and infiltrating immune cells within an understudied immunomodulatory compartment of the CNS and may identify novel therapeutic strategies against CNS autoimmune disease.
多发性硬化症(MS)的临床残疾是由免疫细胞渗入中枢神经系统实质所致。了解中枢神经系统屏障细胞在这一渗透过程中调节免疫细胞激活和进入的机制,可能有助于确定针对MS和其他自身免疫性中枢神经系统疾病的翻译策略。在中枢神经系统炎症期间,免疫细胞从血液中通过一个称为神经血管单位的双屏障结构进行运输。虽然许多人关注的是通过第一道屏障进入,这是一种被称为血脑屏障的特殊内皮壁,但对于免疫细胞如何与第二道屏障相互作用,人们知之甚少。第二道屏障是星形胶质细胞末端足部的一层,被称为胶质限制蛋白。在多发性硬化病变中,免疫细胞在血脑屏障和胶质细胞界限之间的空间内循环,这个空间被称为血管周围空间。在这里,星形胶质细胞可能与渗透的免疫细胞相互作用,以调节它们的功能。通过基因表达分析,我们确定了在多发性硬化症病变中的一种细胞因子白介素1β治疗时,星形胶质细胞上调的免疫细胞受体。我们最有力的候选者之一,JAM-A(JAM-A),是一种免疫细胞受体,调节其他组织中的促炎途径。我的试验数据显示,星形细胞Jam-A结合T细胞,改变蛋白酶和细胞因子水平,已知的模式加剧了多发性硬化症的动物模型。进一步的试验数据显示,星形细胞Jam-A缺失阻止了免疫细胞对胶质细胞界限蛋白的渗透,并在该模型中防止临床残疾。我推测,星形细胞JAM-A推动免疫细胞进入中枢神经系统,形成炎性病变,并导致临床残疾。在目标1中,我将使用RNA测序来测试共培养中星形细胞向T细胞发出的JAM-A信号如何修改两种细胞类型的基因表达网络,然后我将确定JAM-A及其下游候选者如何调节与自身免疫攻击相关的效应器通路。在目标2中,使用转基因和药理学工具,我将确定星形细胞JAM-A如何控制两种中枢神经系统炎症动物模型的病变形成。阻断星形细胞JAM-A和效应器的翻译策略随后将在多发性硬化症的动物模型中进行临床残疾测试。在目标3中,我将使用炎性脊髓病变的实时双光子成像来测量T细胞如何与胶质细胞界限蛋白相互作用。然后我将测试星形细胞Jam-A和效应器是如何调节这些相互作用的。这个K08奖项的目标是在Gareth John博士、Peter Calabresi医学博士的指导下,提高我在神经免疫学和神经胶质生物学方面的专业知识。和Dimitrios Davalos博士学习使用免疫和神经胶质细胞共培养以及体内多光子成像的技术技能,并建立自己的研究小组,专注于星形胶质细胞-免疫细胞信号在自身免疫攻击中的作用。这项K08计划研究了中枢神经系统免疫调节隔区内反应性星形胶质细胞和浸润性免疫细胞之间的一种新的接触介导的相互作用,并可能确定针对中枢神经系统自身免疫性疾病的新治疗策略。

项目成果

期刊论文数量(0)
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Sam H Horng其他文献

Identification and functional characterization of two patterning genes, Zic4 and Ten_m3, in topographic map formation of the visual pathway
视觉通路地形图形成中两个模式基因 Zic4 和 Ten_m3 的识别和功能表征
  • DOI:
  • 发表时间:
    2009
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Sam H Horng
  • 通讯作者:
    Sam H Horng
The Pathophysiology and Clinical Presentation of Multiple Sclerosis
多发性硬化症的病理生理学和临床表现
  • DOI:
  • 发表时间:
    2017
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Sam H Horng;M. Fabian
  • 通讯作者:
    M. Fabian

Sam H Horng的其他文献

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{{ truncateString('Sam H Horng', 18)}}的其他基金

Astrocytic control of lymphocyte migration and differentiation in CNS inflammatory lesions
星形胶质细胞控制中枢神经系统炎症病变中淋巴细胞迁移和分化
  • 批准号:
    10457390
  • 财政年份:
    2018
  • 资助金额:
    $ 19.33万
  • 项目类别:
Astrocytic control of lymphocyte migration and differentiation in CNS inflammatory lesions
星形胶质细胞控制中枢神经系统炎症病变中淋巴细胞迁移和分化
  • 批准号:
    9767294
  • 财政年份:
    2018
  • 资助金额:
    $ 19.33万
  • 项目类别:
Molecular Mechanisms of Visual Thalamic Development
视觉丘脑发育的分子机制
  • 批准号:
    7575237
  • 财政年份:
    2008
  • 资助金额:
    $ 19.33万
  • 项目类别:
Molecular Mechanisms of Visual Thalamic Development
视觉丘脑发育的分子机制
  • 批准号:
    7330233
  • 财政年份:
    2008
  • 资助金额:
    $ 19.33万
  • 项目类别:

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