The Role of TRPV4 in central nervous system immunity and disease

摘要 实验性自身免疫性脑脊髓炎（EAE）是一种CD4 T细胞依赖性模型， 多发性硬化症（MS）。在这些疾病中， 响应被协调朝向中枢神经系统（CNS）髓磷脂。最终 一系列的炎症事件最终导致髓鞘和神经元损伤， 大部分由吞噬免疫细胞如浸润性巨噬细胞和活化的 小胶质细胞这些分子调控炎症反应， 先天细胞亚群仍不清楚。在初步研究中，我们发现， 瞬时受体电位（TRP）阳离子通道，TRPV4由小胶质细胞表达， 细胞和功能，以传播EAE期间的效应炎症反应。这些 数据使我们假设先天免疫细胞表达TRPV 4， 包括循环单核细胞和小胶质细胞，有助于MS的发病机制 并且可以被调节以降低神经炎症的严重性。我们会委聘 三个互补的目的是探索这个假设。首先，我们将确定细胞 TRPV4介导的CNS中神经免疫相互作用的基础， 骨髓嵌合体和我们设计的一种新的鼠试剂，其中TRPV4是 在体内条件性表达。第二，我们将确定治疗效果， EAE期间TRPV4抑制。第三，我们将检查人体组织和材料， 广泛的生物储存库，以评估TRPV4在免疫细胞和MS中的表达 病变这项高度翻译的研究将建立TRPV4的细胞机制。 EAE期间的依赖性免疫激活， 通过TRPV4的神经炎症，以及TRPV4表达模式， 女士因此，这项研究产生了一个独特的机会，以确定一个分子靶点， 神经炎性疾病如MS的合理治疗设计。

Abstract Experimental autoimmune encephalomyelitis (EAE) is a CD4 T cell-dependent model for the human disease multiple sclerosis (MS). In these diseases, a complex immune response is orchestrated toward central nervous system (CNS) myelin. Ultimately, the cascade of inflammatory events culminates in myelin and neuronal damage, mediated in large part by phagocytic immune cells such as infiltrating macrophages and activated microglia. The molecular regulation that governs inflammatory responses by these innate cell subsets remains unclear. In preliminary studies, we have discovered that the Transient Receptor Potential (TRP) cation channel, TRPV4 is expressed by microglial cells and functions to propagate effector inflammatory responses during EAE. These data have led us to hypothesize that expression of TRPV4 by innate immune cells, including circulating monocytes and microglia, contributes to the pathogenesis of MS and can be modulated to reduce the severity of neuro-inflammation. We will employ three complementary aims to explore this hypothesis. First, we will determine the cellular basis of TRPV4-mediated neuro-immune interactions in the CNS using both radiation bone marrow chimeras and a new murine reagent we have designed in which TRPV4 is conditionally expressed in vivo. Second, we will determine the therapeutic effect of TRPV4 inhibition during EAE. Third, we will examine human tissue and material from an extensive bio-repository to assess the expression of TRPV4 in immune cells and MS lesions. This highly translational study will establish the cellular mechanism of TRPV4- dependent immune activation during EAE, the potential for pharmacologic modulation of neuro-inflammation via TRPV4, and the pattern of TRPV4 expression in patients with MS. Thus, this study engenders a unique opportunity to identify a molecular target for the rational design of treatment for neuro-inflammatory diseases such as MS.