Reelin regulation of the crosstalk between the Immune and Nervous systems

大脑和免疫系统很容易对多种内部和外部信号做出反应，并随着这些经历而适应和改变。此外，免疫系统和大脑显然是相互影响的，这种相声对它们的可塑性和行为也有影响。我的总体研究计划侧重于研究免疫和神经可塑性的潜在机制，以及这些机制如何影响大脑和免疫系统功能以及这两个系统之间的相互作用。在这项提议中，我将评估这样一种假设，即Reelin是一种在脑和血浆中表达的细胞外基质蛋白，在调节免疫和神经可塑性以及促进这两个系统之间的相互作用方面发挥着重要作用。Reelin最初被认为是脑发育中的关键蛋白质，后来被证明调节神经可塑性以及成年大脑中GABA能和谷氨酸能系统之间的相互作用。除了大脑，Reelin还在血浆和淋巴细胞中表达，Reelin缺乏的动物似乎在免疫系统中表现出显著的变化。然而，目前还没有关于reelin如何影响免疫系统或大脑和免疫系统之间的串扰的系统研究。我最近的工作已经开始解决这个问题。我们已经证明，糖皮质激素影响特定脑区的reelin表达，并且reelin缺陷也会导致血淋巴细胞膜蛋白聚集的改变。为了直接评估reelin在调节神经和免疫串扰方面的潜在作用，我提出了一系列实验，旨在分析reelin下调对大脑和免疫系统中神经递质受体和转运体的表达和膜聚集的影响，以及对细胞因子(特别是对大脑和外周观察到的细胞因子)释放的影响。在活体系统中，我还将研究与卷轴缺陷相关的认知行为的变化(即物体识别测试)。我还建议给那些因遗传或应用糖皮质激素而导致卷轴蛋白缺陷的动物注射重组卷轴蛋白。在这种情况下，我计划评估注射重组卷轴蛋白能否恢复大脑和免疫可塑性以及行为的变化，这是我们预期在卷轴蛋白缺陷动物身上看到的。

The brain and immune system readily respond to multiple internal and external signals and adapt and change with these experiences. In addition, the immune system and the brain clearly influence each other, and this crosstalk also has an effect in their plasticity and behavior. My general research program focuses on studying the mechanisms underlying immune and neural plasticity, and how these mechanisms affect the brain and immune system functions and the interactions between both systems. In this proposal, I will evaluate the hypothesis that reelin, an extracellular matrix protein expressed both in brain and blood plasma, plays an important role in regulating immune and neural plasticity and in facilitating the crosstalk between both systems. Reelin was first identified as a critical protein in brain development, and thereafter it was shown to regulate neural plasticity and the interaction between GABAergic and glutamatergic systems in the adult brain. In addition to the brain, reelin is also expressed in blood plasma and lymphatic cells, and animals with reelin deficiencies appear to show prominent alterations in their immune system. However, there has been no systematic investigation of how reelin influences the immune system or the crosstalk between the brain and the immune system. My recent work has begun to address this issue. We have shown that glucocorticoids affect reelin expression in specific brain regions and also that reelin deficits bring about alterations in membrane protein clustering in blood lymphocytes. To directly assess the potential role of reelin in regulating neural and immune crosstalk, I propose a series of experiments designed to analyze the effects of reelin downregulation on the expression and membrane clustering of neurotransmitter receptors and transporters located both in brain and the immune system, and on the release of cytokines (particularly on cytokines that are observed both in the brain and periphery). In the case of the in vivo system, I will also study alterations in cognitive behavior associated with reelin deficits (i.e. object recognition test). I also propose to administer recombinant reelin to animals where a reelin deficit has been induced either genetically or through the application of glucocorticoids. In this case, I plan to assess whether the administration of recombinant reelin can restore the alterations in brain and immune plasticity and also on behavior, that we expect to see in reelin-deficit animals.