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Molecular Genetics of Lyme Arthritis

莱姆关节炎的分子遗传学

基本信息

批准号：
10532743
负责人：
Janis J. Weis
金额：
$ 39.98万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-01-15 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10532743
关键词：
Address Alleles Arthritis BCL6 gene Bone Density Borrelia burgdorferi C57BL/6 Mouse CDKN2A gene Carditis Cells Chromosome Mapping Chromosomes Chronic Disease Clinical Complex Congenic Mice Cyclin-Dependent Kinases Development Disease Fatigue GDF8 gene Gene Cluster Gene Expression Gene Silencing Genes Genetic Genetic Polymorphism Goals Human Immune response In Vitro Inbred C3H Mice Individual Infection Inflammation Interferons Joints Knockout Mice Link Localized Skin Lesion Lyme Arthritis Lyme Disease Mediator Molecular Genetics Mus Muscle Muscle Development Musculoskeletal Myeloid Cells Neuropathy Order Spirochaetales Pain Pathogenesis Pathogenicity Pathology Pathway interactions Patients Production Proteins Quantitative Trait Loci RNA Interference Radiation Chimera Reading Frames Recombinants Regulation Regulatory Pathway Reporting Research Role Sampling Severities Skeletal Muscle Source Symptoms Synovial Fluid TP53 gene Tissues Up-Regulation bone congenic experimental study forward genetics genetic approach genetic element in vitro testing in vivo evaluation inhibitor insight joint function muscle form new therapeutic target novel positional cloning prevent skin lesion small molecule inhibitor therapeutic target tick bite tick borne spirochete

项目摘要

PROJECT SUMMARY / ABSTRACT Lyme disease is caused by the tick borne spirochete Borrelia burgdorferi and there are estimated to be 300,000 cases/year in the US. It is associated with a spectrum of clinical symptoms of varying severities, ranging from localized skin lesion to disseminated infection including secondary skin lesions, arthritis, neuropathies, and carditis. It is apparent that genetically regulated responses of the host contribute to the severity of symptoms. We have taken a forward genetics approach to identify allelic genes that determine the difference in Lyme arthritis between the severely arthritic C3H mouse and the mildly arthritic C57BL/6 (B6) mouse. This analysis has identified Quantitative Trait Loci on several chromosomes, including the Bbaa1 locus on Chr 4, which encompasses the Type I IFN gene cluster. Congenic mouse lines in which the C3H Bbaa1 allele was introgressed onto the B6 background (B6.C3H-Bbaa1) confirmed the presence of a genetic element in this locus that regulates arthritis through expression of IFNβ, a Type I IFN. As the C3H and B6 IFNβ genes lack polymorphisms, any expression differences must be regulated by a linked genetic element. Advanced, interval specific recombinant congenic lines (ISRCL) have narrowed the physical region associated with Bbaa1 to 2.2 Mbp and identified the Cyclin Dependent Kinase Inhibitory gene, Cdkn2a, as a candidate regulator of IFNβ expression and determinant of the severity of Lyme arthritis. A variety of experiments demonstrated that the Bbaa1 impact on IFNβ expression was manifest through B. burgdorferi stimulation of myeloid cells, but that an additional, downstream mediator of arthritis required distinct activation of resident cells of the joint tissues. Independent studies characterized the arthritis-inducing activity of IFNβ as myostatin (MSTN). MSTN is well characterize as modulating skeletal muscle development, but has also been implicated in chronic disease and inflammation. We will utilize the B6.C3-Bbaa1 ISRCLs to characterize the mechanism by which products of the Cdkn2a locus regulate IFNβ production in myeloid cells, and, in turn, the mechanism by which the downstream effector MSTN modulates Lyme arthritis development. We propose a combination of lineage-specific expression analysis, silencing of gene expression, development of targeted KO mice, and the use of small molecule inhibitors in order to define the complex interactions involved in Lyme arthritis development. Our findings may provide insight into other pathologies driven by Type I IFN, which could also implicate unexpected pathways involving Cdkn2a and MTSN.

项目摘要/摘要