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.

项目摘要 莱姆病（LD）是美国最普遍的tick传播疾病（〜300,000-475,000例）是 由Borreliella burgdorferi（BB）Sensu Lato（S.L.）复合体的螺旋体引起。当早期LD诊断为 错过，它未经治疗，LD变为慢性。人疫苗不可用。抗菌治疗 慢性/持续感染通常没有回报。 LD可能会持续多年，以皮肤病变形式出现， 关节炎，心脏炎和/或莱姆神经性脂肪性病（LNB）。中央（中枢神经系统）和周围神经系统 （PN）受到影响，这会导致头痛，疲劳，记忆力丧失，抑郁，面神经麻痹 其他的。不完全了解LNB的主要原因是有限的动物可用性有限 型号。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。但是，成本问题，试剂可用性，不可再生的遗传背景和道德问题 担忧限制了他们的使用。实验室小鼠菌株不会发展神经系统临床体征和脑炎。 当前的知识差距是缺乏合适的LNB小鼠模型。总体目标是发展 将允许进入中枢神经系统/PN的小鼠模型，在神经中发展炎症病变 组织，表现出神经系统迹象。在长达3年的初步研究中，协作十字架（CC） 资源（32行； 〜230只小鼠）广泛用于识别LNB的小鼠模型。数据显示 超过30％的CC线E小鼠被BB感染了6个月，包括小鼠 BB感染时表现出神经系统迹象，在大脑中出现明显的炎症性病变，脊柱 绳索和周围神经。在此应用中，建议使用9行测试4种不同的BB菌株 已经显示出BB感染引起的神经组织炎症。还建议包括新的 尚未测试的8条CC线，因此将使用40 cc线（32+8）来识别遗传 通过定量性状基因座Anlaysis导致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.将产生独特的LNB 表型。 SA2：将造成LNB的遗传因素定位。 这种方法是创新的，CC资源从未在LD研究领域使用。识别 单个CC线始终显示神经组织中炎症和/或螺旋体的存在 在LNB领域，将被认为是一个重大进步。预计映射分辨率将确定 有信心的因果区域，识别QTL之间的数量，效果大小以及关系将有助于 指导随后的调查，并为未来的R01申请提供基础。提议 研究很重要，因为LNB的小鼠模型将允许科学界研究LNB 发病机理更详细，并为R01应用提供基础。