The Role of TRPV4 in central nervous system immunity and disease

TRPV4在中枢神经系统免疫和疾病中的作用

• 批准号: 10240568
• 负责人: Gregory Wu
• 金额: $ 40.17万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10240568
• 关键词: Address; Affect; Afferent Neurons; American; Animal Model; Antigen-Antibody Complex; Attenuated; Autopsy; Blood - brain barrier anatomy; Blood specimen; Bone Marrow; Brain; CCL2 gene; CD4 Positive T Lymphocytes; Calcium Channel; Cations; Cell physiology; Cells; Central Nervous System Diseases; Cerebrospinal Fluid; Chimera organism; Collection; Data; Demyelinations; Development; Disease; Event; Experimental Autoimmune Encephalomyelitis; Goals; Health; Immune; Immune response; Immune system; Immunity; Immunologics; In Vitro; Individual; Inflammation; Inflammatory; Inflammatory Response; Innate Immune Response; Link; Mediating; Mediator of activation protein; Microglia; Modeling; Molecular; Molecular Target; Multiple Sclerosis; Multiple Sclerosis Lesions; Mus; Myelin; Myeloid Cells; Nature; Nervous system structure; Neuraxis; Neuroimmune; Neurologic Process; Neurons; Pathogenesis; Patients; Pattern; Peripheral; Peripheral nerve injury; Phagocytes; Pharmacology; Phase; Phosphorylation; Physiological; Play; Radiation; Reagent; Regulation; Role; Sampling; Severities; Specimen; Spinal Cord; TRP channel; Testing; Therapeutic Effect; Tissue Microarray; Tissues; Universities; Vanilloid; Vascular Endothelial Cell; Washington; base; biobank; design; disability; human disease; human tissue; immune activation; in vivo; macrophage; member; monocyte; multiple sclerosis patient; neuroinflammation; neuroregulation; optimal treatments; p38 Mitogen Activated Protein Kinase; pain signal; prevent; receptor; recombinase-mediated cassette exchange; response; therapeutic target; therapy design; translational study; treatment strategy

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.

摘要 实验性自身免疫性脑脊髓炎(EAE)是一种CD4T细胞依赖的动物模型 人类疾病多发性硬化症(MS)。在这些疾病中，一种复杂的免疫系统 反应是向中枢神经系统(CNS)髓鞘协调的。归根结底， 一连串的炎症事件最终导致髓鞘和神经元损伤，介导了 很大一部分是由吞噬免疫细胞等渗入并激活的巨噬细胞 小胶质细胞。通过这些调控炎症反应的分子调控 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 在EAE期间传播效应器炎症反应的细胞和功能。这些 数据让我们假设TRPV4是由先天免疫细胞表达的， 包括循环单核细胞和小胶质细胞，参与了MS的发病 并且可以被调节以降低神经炎症的严重程度。我们将聘用 探索这一假设有三个相辅相成的目标。首先，我们将确定细胞 TRPV4介导的中枢神经系统免疫相互作用的基础 骨髓嵌合体和我们设计的一种新的小鼠试剂，其中TRPV4是 在体内有条件地表达。第二，我们将确定其治疗效果。 在EAE过程中抑制TRPV4。第三，我们将检查人体组织和材料 广泛的生物信息库评估TRPV4在免疫细胞和多发性硬化中的表达 损伤。这项高度翻译的研究将建立TRPV4的细胞机制- EAE过程中的依赖免疫激活，药物调节的可能性 TRPV4介导的神经炎症及TRPV4在慢性粒细胞白血病患者中的表达模式 因此，这项研究提供了一个独特的机会来确定一个分子靶标 合理设计MS等神经炎性疾病的治疗方案。

项目成果

Miswiring of Merkel cell and pruriceptive C fiber drives the itch-scratch cycle.

• DOI: 10.1126/scitranslmed.abn4819
• 发表时间: 2022-07-13
• 期刊: SCIENCE TRANSLATIONAL MEDICINE
• 影响因子: 17.1
• 作者: Feng, Jing;Zhao, Yonghui;Xie, Zili;Zang, Kaikai;Sviben, Sanja;Hu, Xueming;Fitzpatrick, James A. J.;Wen, Lu;Liu, Yifei;Wang, Ting;Lawson, Katy;Liu, Qin;Yan, Yan;Dong, Xinzhong;Han, Liang;Wu, Gregory F.;Kim, Brian S.;Hu, Hongzhen
• 通讯作者: Hu, Hongzhen

MrgprA3-expressing pruriceptors drive pruritogen-induced alloknesis through mechanosensitive Piezo2 channel.

• DOI: 10.1016/j.celrep.2023.112283
• 发表时间: 2023-04-25
• 期刊: Cell reports
• 影响因子: 8.8

The Role of B Cells in Primary Progressive Multiple Sclerosis.

• DOI: 10.3389/fneur.2021.680581
• 发表时间: 2021
• 期刊: Frontiers in neurology
• 影响因子: 3.4
• 作者: Holloman JP;Axtell RC;Monson NL;Wu GF
• 通讯作者: Wu GF

X-tra X: An escape to autoimmunity.

X-tra X：逃避自身免疫。

• DOI: 10.1172/jci130312
• 发表时间: 2019
• 期刊: The Journal of clinical investigation
• 作者: Wu,GregoryF

Bcl6 controls meningeal Th17-B cell interaction in murine neuroinflammation.

• DOI: 10.1073/pnas.2023174118
• 发表时间: 2021-09-07
• 期刊: Proceedings of the National Academy of Sciences of the United States of America
• 影响因子: 11.1
• 作者: Hartlehnert M;Börsch AL;Li X;Burmeister M;Gerwien H;Schafflick D;Heming M;Lu IN;Narayanan V;Strecker JK;Kolz A;Peters A;Wu GF;Wiendl H;Sorokin L;Meyer Zu Horste G
• 通讯作者: Meyer Zu Horste G