MicroRNAs induced in response to Borrelia burgdorferi

响应伯氏疏螺旋体诱导的 MicroRNA

基本信息

批准号：
9164595
负责人：
Catherine Ayn Brissette
金额：
$ 17.38万
依托单位：
UNIVERSITY OF NORTH DAKOTA
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：
2016-06-23 至 2018-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9164595
关键词：
Address Affect Aftercare Antibiotic Therapy Antibiotics Area Arthropods Astrocytes Atlases Bacteria Bioinformatics Blood - brain barrier anatomy Borrelia burgdorferi Brain Cell Adhesion Central Nervous System Infections Clinical Trials Cognition Communication Data Disease Encephalitis Equilibrium Facial nerve structure Fatigue Genes Health Health Care Costs Homeostasis Human Impaired cognition Incidence Infection Infectious Agent Inflammation Inflammation Mediators Inflammatory Knowledge Lead Life Link Lyme Disease Maintenance Mediating Medical Memory Meningitis MicroRNAs Microglia Midwestern United States Modeling Musculoskeletal Pain Neuraxis Neurocognitive Neuroglia Neurologic Neurons New England North America Pain Paralysed Pathway interactions Patients Play Publishing Rattus Role Signal Transduction Symptoms Syndrome System Technology Testing Tick-Borne Diseases Ticks Tight Junctions Tissues Vaccines Work Xenodiagnosis cost experience genome-wide glial activation in vivo nervous system disorder neuroinflammation neuropathology next generation sequencing novel pathogen persistent symptom response response to injury tissue repair vector vector control

Address Affect Aftercare Antibiotic Therapy Antibiotics Area Arthropods Astrocytes Atlases Bacteria Bioinformatics Blood - brain barrier anatomy Borrelia burgdorferi Brain Cell Adhesion Central Nervous System Infections Clinical Trials Cognition Communication Data Disease Encephalitis Equilibrium Facial nerve structure Fatigue Genes Health Health Care Costs Homeostasis Human Impaired cognition Incidence Infection Infectious Agent Inflammation Inflammation Mediators Inflammatory Knowledge Lead Life Link Lyme Disease Maintenance Mediating Medical Memory Meningitis MicroRNAs Microglia Midwestern United States Modeling Musculoskeletal Pain Neuraxis Neurocognitive Neuroglia Neurologic Neurons New England North America Pain Paralysed Pathway interactions Patients Play Publishing Rattus Role Signal Transduction Symptoms Syndrome System Technology Testing Tick-Borne Diseases Ticks Tight Junctions Tissues Vaccines Work Xenodiagnosis cost experience genome-wide glial activation in vivo nervous system disorder neuroinflammation neuropathology next generation sequencing novel pathogen persistent symptom response response to injury tissue repair vector vector control

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项目摘要

PROJECT SUMMARY Lyme disease is the most prevalent arthropod-borne disease in the US. The causative agent of the disease is the bacterium Borrelia burgdorferi (Bb), which affects multiple tissues including the central nervous system (CNS). Lingering symptoms including pain, fatigue, and difficulties with memory and cognition persist in up to 20% of all patients treated with antibiotics. The cause of this Post-Treatment Lyme Disease Syndrome (PTLDS) is unclear and controversial. We propose that live bacteria are not required to drive persistent inflammation in the CNS. Using a rat model of neuroborreliosis, we demonstrated that CNS inflammation persists in the absence of live bacteria. What drives the persistent inflammation? We also found Bb can induce changes in microRNA expression changes in astrocytes including miR-122-5p, miR-135a-3p, miR-135a-5p, miR-143-3p and miR-146b-5p. Targets of these microRNAs include genes involved in cell adhesion, tight junctions, cell signaling, and response to infection. Astrocytes are key players in response to injury, neuronal support, and tissue repair. Our working hypothesis is that neurological symptoms are perpetuated by Bb-induced microRNAs that lead to a persistent neuroinflammatory response. We will test this hypothesis with 2 Specific Aims. In Specific Aim 1 we will develop a complete atlas of the glial- specific microRNAs and their targets induced Bb-infected brain relative to uninfected brain. In the second Specific Aim, we will manipulate microRNA-mediated inflammatory mediators in primary glial cells through the use of specific microRNA antagomirs, demonstrating the mechanistic link between altered microRNA expression and inflammation. Our long-term objective is to modulate host CNS responses to Bb in vivo through manipulation of microRNA expression. By elucidating the specific microRNAs that contribute to neuroinflammation, we will provide novel targets for Lyme disease therapy. MicroRNA mimics and antagonists are already in human trials, demonstrating the potential feasibility of such therapies.

项目摘要莱姆病是美国最普遍的节肢动物传播疾病。该疾病的病因是细菌Borrelia burgdorferi（BB），它影响包括中枢神经系统在内的多个组织（CNS）。挥之不去的症状，包括疼痛，疲劳以及记忆和认知的困难持续存在所有接受抗生素治疗的患者中有20％。这种治疗后莱姆病综合征的原因（PTLD）尚不清楚且有争议。我们建议不需要活细菌驱动中枢神经系统的持续炎症。使用大鼠神经红细胞增多的模型，我们证明了CNS炎症在没有活细菌的情况下持续存在。是什么驱动持续的炎症？我们还发现BB可以诱导microRNA表达的变化星形胶质细胞的变化，包括miR-122-5p，miR-135a-3p，mir-135a-5p，miR-143-3p和miR-146b-5p。这些microRNA的靶标包括参与细胞粘附，紧密连接，细胞信号传导和对感染的反应。星形胶质细胞是响应损伤，神经元支撑和组织修复的主要参与者。我们的工作假设是，神经系统症状是由BB诱导的microRNA永久存在的导致持续的神经炎症反应。我们将以2个特定目标检验这一假设。在特定的目标1中，我们将开发一个完整的胶质地图集特定的microRNA及其靶标相对于未感染的大脑引起的BB感染大脑。在第二个具体目的，我们将通过原代神经胶质细胞中的microRNA介导的炎症介质通过使用特定的microRNA Antagomirs，证明了改变microRNA之间的机械联系表达和炎症。我们的长期目标是通过操纵microRNA来调节宿主中枢神经系统对BB的响应表达。通过阐明有助于神经炎症的特定microRNA，我们将提供新颖的莱姆病疗法的靶标。 microRNA模仿和拮抗剂已经在人类试验中，证明这种疗法的潜在可行性。