Exploring the Collaborative Cross resource to identify different phenotypes of Lyme neuroborreliosis and disease-contributing genetic factors

探索协作交叉资源以确定莱姆神经疏螺旋体病的不同表型和疾病致病遗传因素

• 批准号: 10666026
• 负责人: Artem Rogovsky
• 金额: $ 22.31万
• 依托单位: TEXAS A&M AGRILIFE RESEARCH
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10666026
• 关键词: Affect; Animal Model; Animals; Arthritis; Borrelia burgdorferi; Borrelia garinii; Borrelia mayonii; Brain; Carditis; Cells; Central Nervous System; Chronic; Clinical; Communities; Complex; Control Locus; Data; Development; Disease; Dura Mater; Encephalitis; Ethics; Exhibits; Facial nerve structure; Fatigue; Foundations; Funding; Future; Genetic; Genetic Recombination; Genetic Variation; Goals; Headache; Human; Inbred C3H Mice; Infection; Inflammation; Inflammatory; Interferons; Invaded; Investigation; Knowledge; Laboratory mice; Learning Disabilities; Left; Lesion; Leucocytic infiltrate; Limb structure; Lyme Disease; Lyme Neuroborreliosis; Lyme disease diagnosis; Maps; Memory Loss; Meningitis; Mental Depression; Mission; Modeling; Mouse Strains; Mus; Muscle Weakness; Nerve; Neurocognitive; Neurologic; Neurologic Signs; Neurologic Symptoms; Order Spirochaetales; Pain; Paralysed; Pathogenesis; Pathogenicity; Patients; Peripheral; Peripheral Nerves; Peripheral Nervous System; Phenotype; Predisposition; Process; Quantitative Trait Loci; Reagent; Research; Resolution; Resource Development; Resources; Sensory; Spinal Cord; Symptoms; Testing; Tick-Borne Diseases; Tissues; Treatment Protocols; Trigeminal System; United States National Institutes of Health; Up-Regulation; Vaccines; Work; antimicrobial; behavioral study; brain parenchyma; chronic infection; cost; cytokine; diagnostic tool; flu; innovation; insight; lyme pathogenesis; mouse development; mouse model; neural; neuroinflammation; nonhuman primate; novel diagnostics; novel therapeutics; pathogen; permissiveness; response; skin lesion; tool

PROJECT SUMMARY Lyme disease (LD), the most prevalent tick-borne illness in the US (~300,000-475,000 annual cases), is caused by spirochetes of Borreliella burgdorferi (Bb) sensu lato (s.l.) complex. When early LD diagnosis is missed, it is left untreated and LD becomes chronic. Human vaccine is unavailable. Antimicrobial treatment of chronic/persistent infection is often unrewarding. LD may last for years, presenting itself as skin lesions, arthritis, carditis, and/or Lyme neuroborreliosis (LNB). Both central (CNS) and peripheral nervous systems (PNS) are affected, which results in headache, fatigue, memory loss, depression, facial nerve palsy among others. The main reason for incomplete understanding of LNB is the limited availability of adequate animal models. Nonhuman primates are the only model that demonstrates similarities to clinical manifestations of human LNB. However, issues of cost, reagents availability, non-reproducible genetic backgrounds, and ethical concerns limit their use. Laboratory mouse strains do not develop neurological clinical signs and encephalitis. The current knowledge gap is the lack of suitable mouse models of LNB. The overall objective is to develop mouse model that will be permissive to Bb entry into the CNS/PNS, develop inflammatory lesions in the neural tissues, and exhibit neurological signs. In the preliminary 3-year-long study, the Collaborative Cross (CC) resource (32 lines; ~230 mice) was extensively used to identify the mouse model of LNB. The data showed that over 30% of mice of CC line E, which were infected with Bb for 6 months, including the mouse that exhibited neurological signs upon Bb infection, developed significant inflammatory lesions in the brain, spinal cord, and peripheral nerves. In this application, it is proposed to test 4 different Bb strains using the 9 lines that have already shown Bb infection-induced inflammation in the neural tissues. It is also proposed to include new 8 CC lines that have not been tested, so that a total of 40 CC lines (32+8) will be used to identify genetic factors contributing to LNB via quantitative trait locus anlaysis. The following Specific Aims will be pursued: SA1: Determine if CC lines infected with various strains of Bb s.l. will produce distinct LNB phenotypes. SA2: Localize genetic factors contributing to LNB. This approach is innovative s the CC resource has never been utilized in the LD research field. Identifying a single CC line that consistently shows the presence of inflammation and/or spirochetes in the neural tissues will be considered a substantial advance in the field of LNB. The mapping resolution is expected to identify causal regions with confidence, and the number, effect sizes, and relationship among QTL identified will help guide subsequent investigations and provide the foundation for a future R01 application. The proposed research is significant because a mouse model of LNB will allow the scientific community to study the LNB pathogenesis in much greater detail and and provide the foundation for a R01 applications.

项目概要 莱姆病 (LD) 是美国最常见的蜱传疾病（每年约 300,000-475,000 例病例）， 由伯氏疏螺旋体 (Bb) sensu lato (s.l.) 复合体螺旋体引起。当早期 LD 诊断为 错过了，就得不到治疗，LD 就会变成慢性。人类疫苗尚无。抗菌处理 慢性/持续感染通常是没有回报的。 LD 可能持续数年，表现为皮肤损伤， 关节炎、心脏炎和/或莱姆神经疏螺旋体病 (LNB)。中枢 (CNS) 和周围神经系统 (PNS) 受到影响，导致头痛、疲劳、记忆力减退、抑郁、面神经麻痹 其他的。对 LNB 不完全了解的主要原因是缺乏足够的动物 模型。非人类灵长类动物是唯一表现出与临床表现相似的模型 人类 LNB。然而，成本、试剂可用性、不可重复的遗传背景和伦理问题 担忧限制了它们的使用。实验室小鼠品系不会出现神经临床症状和脑炎。 目前的知识差距是缺乏合适的 LNB 小鼠模型。总体目标是发展 允许 Bb 进入 CNS/PNS 的小鼠模型，在神经系统中产生炎症损伤 组织，并表现出神经系统症状。在为期 3 年的初步研究中，协作交叉 (CC) 资源（32 个系；约 230 只小鼠）被广泛用于鉴定 LNB 小鼠模型。数据显示 超过30%的CC系E小鼠感染了Bb 6个月，其中包括 Bb 感染后表现出神经系统症状，在大脑、脊髓中出现明显的炎症病变 脊髓和周围神经。在此应用中，建议使用 9 个品系测试 4 种不同的 Bb 菌株， 已经表明 Bb 感染会引起神经组织炎症。还建议纳入新的 8 个未经测试的 CC 系，因此总共 40 个 CC 系（32+8）将用于鉴定遗传 通过数量性状基因座分析影响 LNB 的因素。将追求以下具体目标： SA1：确定 CC 系是否感染了各种 Bb s.l 菌株。将产生独特的LNB 表型。 SA2：定位导致 LNB 的遗传因素。 这种方法是创新的，因为 CC 资源从未在 LD 研究领域得到利用。识别一个 单一 CC 线一致显示神经组织中存在炎症和/或螺旋体 将被视为 LNB 领域的重大进步。映射分辨率预计将确定 具有置信度的因果区域，以及确定的 QTL 的数量、效应大小和关系将有助于 指导后续调查，为未来R01应用奠定基础。拟议的 研究意义重大，因为 LNB 小鼠模型将使科学界能够研究 LNB 更详细地阐述了发病机制，并为 R01 应用奠定了基础。