Project 3

项目3

基本信息

批准号：
9924574
负责人：
Catherine Ayn Brissette
金额：
$ 29.25万
依托单位：
UNIVERSITY OF NORTH DAKOTA
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至 2021-08-04
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9924574
关键词：
Acetates Address Amber Animals Antibiotic Therapy Antibiotics Antigens Apoptosis Arbovirus Infections Area Arthritis Bacteria Borrelia burgdorferi Brain Case Study Cell Communication Cell Death Cells Centers for Disease Control and Prevention (U.S.)Central Nervous System Infections Cessation of life Cognition Cognitive deficits Data Disease Disease Progression Down-Regulation Encapsulated Event Facial nerve structure Gap Junctions Health Care Costs Human Human Bites Impaired cognition In Vitro Infectious Agent Inflammation Inflammatory Inflammatory Response Intervention Investigation Joints Knowledge Laboratories Lead Link Lyme Arthritis Lyme Disease Lyme Neuroborreliosis Mediating Memory impairment Meningitis Methodology Modeling Mus Nerve Degeneration Nervous System Physiology Neuraxis Neurodegenerative Disorders Neuroglia Neurologic Neurologic Dysfunctions Neurons Order Spirochaetales Paralysed Pathogenesis Pathology Pathway interactions Patients Personal Satisfaction Pharmacology Prevention Preventive Intervention Proteins Psyche structure Rattus Reagent Refractory Rodent Model Signal Pathway Societies Speed Supplementation Symptoms Syndrome Testing Therapeutic Ticks Time Tissues arthropod-borne axon injury behavior test cell type cytokine experience experimental study glial activation in vivo inflammatory marker innovation interdisciplinary approach knowledge base microorganism nervous system disorder neuroinflammation neuron apoptosis neuron loss neuropathology nonhuman primate pathogen persistent symptom prevent public health relevance relating to nervous system response restoration therapeutic development therapy development vector-borne pathogen

Acetates Address Amber Animals Antibiotic Therapy Antibiotics Antigens Apoptosis Arbovirus Infections Area Arthritis Bacteria Borrelia burgdorferi Brain Case Study Cell Communication Cell Death Cells Centers for Disease Control and Prevention (U.S.)Central Nervous System Infections Cessation of life Cognition Cognitive deficits Data Disease Disease Progression Down-Regulation Encapsulated Event Facial nerve structure Gap Junctions Health Care Costs Human Human Bites Impaired cognition In Vitro Infectious Agent Inflammation Inflammatory Inflammatory Response Intervention Investigation Joints Knowledge Laboratories Lead Link Lyme Arthritis Lyme Disease Lyme Neuroborreliosis Mediating Memory impairment Meningitis Methodology Modeling Mus Nerve Degeneration Nervous System Physiology Neuraxis Neurodegenerative Disorders Neuroglia Neurologic Neurologic Dysfunctions Neurons Order Spirochaetales Paralysed Pathogenesis Pathology Pathway interactions Patients Personal Satisfaction Pharmacology Prevention Preventive Intervention Proteins Psyche structure Rattus Reagent Refractory Rodent Model Signal Pathway Societies Speed Supplementation Symptoms Syndrome Testing Therapeutic Ticks Time Tissues arthropod-borne axon injury behavior test cell type cytokine experience experimental study glial activation in vivo inflammatory marker innovation interdisciplinary approach knowledge base microorganism nervous system disorder neuroinflammation neuron apoptosis neuron loss neuropathology nonhuman primate pathogen persistent symptom prevent public health relevance relating to nervous system response restoration therapeutic development therapy development vector-borne pathogen

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项目摘要

PROJECT SUMMARY Lyme disease is the most prevalent arthropod-borne disease in the US with more that 30,000 cases reported to the Centers for Disease Control and Prevention in 2010. The causative agent of the disease is Borrelia burgdorferi (Bb) and is transmitted to humans by the bite of infected ticks. Treatment with antibiotics during the initial stage of the disease is effective, although about 25% of the patients treated with antibiotics continue to suffer from arthritis and other post- Lyme disease syndromes; of those patients treated for neuroborreliosis, many experience lingering symptoms including memory impairment and changes in cognition. Recently, our laboratory has demonstrated that 1) Bb can be detected in the brains of infected rats; 2) Bb can cause neuroinflammatory changes in the brain that recapitulate those seen in human patients and nonhuman primate models; and 3) antibiotic-killed Bb can induce an inflammatory response in the brain, suggesting that dead microorganisms and spirochetal debris that remain after antibiotic treatment can contribute to neural pathology. Our central hypothesis is that Lyme neuroborreliosis results from a sustained Bb-induced neuroinflammatory response in the absence of live microorganisms. We believe that the inflammation and lingering symptoms of neuroborreliosis are due to the persistence of bacterial debris following antibiotic treatment. We have generated several reagents and methodologies to test this hypothesis with 3 Specific Aims. In Specific Aim 1 we will characterize the extent of antibiotic-killed Bb-induced inflammation and persistence of spirochetal debris in the brains of rats. In the second Specific Aim we will quantify neuronal apoptosis and cognitive deficits caused by antibiotic-killed Bb. Finally, in Specific Aim 3 we will determine the signaling pathways mediating Bb-induced neuroinflammation and apoptosis. Our findings will contribute to the knowledge base necessary for the development of intervention strategies for prevention and potentially treatment of post-Lyme disease neurological syndromes.

项目摘要莱姆病是美国最普遍的节肢动物传播疾病，有30,000例报道到2010年疾病控制与预防中心。 Burgdorferi（BB），并被感染的壁虱咬伤。在疾病的初始阶段是有效的，尽管大约25％的接受抗生素治疗的患者继续患有关节炎和其他后疾病综合症；在那些接受神经性治疗的患者中，许多经历挥之不去的症状，包括记忆障碍和认知变化。最近，我们的实验室证明1）可以在感染大鼠的大脑中检测到BB； 2）BB可能导致大脑的神经炎症变化概括了人类患者和非人类灵长类动物模型； 3）抗生素杀死的BB可以诱导大脑的炎症反应，表明死亡抗生素治疗后保留的微生物和螺旋碎片可导致神经病理。我们的中心假设是，莱姆神经性病是由持续BB诱导的在没有活微生物的情况下，神经炎症反应。我们相信炎症神经红细胞病的挥之不去的症状是由于抗生素后细菌碎屑的持续性造成的治疗。我们已经生成了几种试剂和方法，以三个特定目的测试该假设。在具体目的1我们将表征抗生素杀死的BB诱导的炎症和持久性的程度大鼠大脑中的螺旋碎片。在第二个特定目的中，我们将量化神经元凋亡和由抗生素杀死的BB引起的认知缺陷。最后，在特定目标3中，我们将确定信号传导介导BB诱导的神经炎症和凋亡的途径。我们的发现将有助于开发预防干预策略所必需的知识基础治疗lyme后疾病神经系统综合征。