Molecular Genetics of Lyme Arthritis
Molecular Genetics of Lyme Arthritis
批准号:
10532743
负责人:
Janis J. Weis
金额:
$39.98万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2020
资助国家:
美国
项目状态:
已结题
起止时间:
2020-01-15 至 2024-11-30
关键词:
AddressAllelesArthritisBCL6 geneBone DensityBorrelia burgdorferiC57BL/6 MouseCDKN2A geneCarditisCellsChromosome MappingChromosomesChronic DiseaseClinicalComplexCongenic MiceCyclin-Dependent KinasesDevelopmentDiseaseFatigueGDF8 geneGene ClusterGene ExpressionGene SilencingGenesGeneticGenetic PolymorphismGoalsHumanImmune responseIn VitroInbred C3H MiceIndividualInfectionInflammationInterferonsJointsKnockout MiceLinkLocalized Skin LesionLyme ArthritisLyme DiseaseMediatorMolecular GeneticsMusMuscleMuscle DevelopmentMusculoskeletalMyeloid CellsNeuropathyOrder SpirochaetalesPainPathogenesisPathogenicityPathologyPathway interactionsPatientsProductionProteinsQuantitative Trait LociRNA InterferenceRadiation ChimeraReading FramesRecombinantsRegulationRegulatory PathwayReportingResearchRoleSamplingSeveritiesSkeletal MuscleSourceSymptomsSynovial FluidTP53 geneTissuesUp-Regulationbonecongenicexperimental studyforward geneticsgenetic approachgenetic elementin vitro testingin vivo evaluationinhibitorinsightjoint functionmuscle formnew therapeutic targetnovelpositional cloningpreventskin lesionsmall molecule inhibitortherapeutic targettick bitetick borne spirochete
中文摘要
项目概要/摘要
莱姆病是由蜱传播的螺旋体伯氏疏螺旋体引起的,
美国每年30万例。它与一系列不同严重程度的临床症状有关,
范围从局部皮肤损伤到播散性感染,包括继发性皮肤损伤,关节炎,
神经病和心脏炎很明显,宿主的遗传调节反应有助于宿主的免疫应答。
症状的严重程度。我们已经采取了正向遗传学方法来鉴定决定基因的等位基因。
严重关节炎C3 H小鼠和轻度关节炎C57 BL/6(B6)之间莱姆关节炎的差异
老鼠.该分析已经确定了几条染色体上的数量性状位点,包括Bbaa 1位点
在Chr 4上,其包括I型IFN基因簇。其中C3 H Bbaa 1
等位基因渗入到B6背景(B6. C3 H-Bbaa 1)中,证实了遗传元件的存在
在这个基因座中,通过表达IFNβ(一种I型IFN)调节关节炎。由于C3 H和B6 IFNβ基因
由于缺乏多态性,任何表达差异都必须由连锁的遗传元件调节。先进的,
间隔特异性重组同源系(ISRCL)缩小了与Bbaa 1相关的物理区域
到2.2 Mbp,并确定了细胞周期蛋白依赖性激酶抑制基因Cdkn 2a,作为一个候选调节因子,
干扰素β表达与莱姆关节炎严重程度的关系各种实验表明,
Bbaa 1对IFNβ表达影响通过B表现出来。burgdorferi刺激骨髓细胞,但
关节炎的另外的下游介质需要关节组织的驻留细胞的独特激活。
独立研究将IFNβ的关节炎诱导活性表征为肌肉生长抑制素(MSTK)。妈妈很好
其特征在于调节骨骼肌发育,但也涉及慢性疾病,
炎症我们将利用B6.C3-Bbaa 1 ISRCL来表征
Cdkn 2a基因座调节髓样细胞中IFNβ的产生,反过来,下游IFN β表达的机制也是如此。
效应器MMPs调节莱姆关节炎的发展。我们提出了一个组合的血统特异性
基因表达分析、基因表达沉默、靶向KO小鼠的开发以及小基因敲除的应用。
分子抑制剂,以确定复杂的相互作用参与莱姆病关节炎的发展。我们
这些发现可能为I型IFN驱动的其他病理提供了深入了解,这也可能涉及意想不到的
涉及Cdkn 2a和MTSN的途径。
英文摘要
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.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
Molecular Genetics of Lyme Arthritis
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批准号:10308027
-
项目类别:
-
资助金额:$39.38万
-
财政年份:2020
-
负责人:Janis J. Weis
-
依托单位:
Molecular Genetics of Lyme Arthritis
-
批准号:10084279
-
项目类别:
-
资助金额:$38.65万
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财政年份:2020
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负责人:Janis J. Weis
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依托单位:
Molecular Genetics of Lyme Arthritis
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批准号:9887063
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项目类别:
-
资助金额:$41.15万
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财政年份:2020
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负责人:Janis J. Weis
-
依托单位:
Role of Zfp318 in the functional development of B cells
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批准号:8990957
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项目类别:
-
资助金额:$18.63万
-
财政年份:2015
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负责人:Janis J. Weis
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依托单位:
Training Program in Microbial Pathogenesis
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批准号:6944059
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项目类别:
-
资助金额:$24.64万
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财政年份:2004
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负责人:Janis J. Weis
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依托单位:
Training Program in Microbial Pathogenesis
-
批准号:6799503
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项目类别:
-
资助金额:$24.62万
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财政年份:2004
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负责人:Janis J. Weis
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依托单位:
Training Program in Microbial Pathogenesis
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批准号:8111237
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项目类别:
-
资助金额:$27.35万
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财政年份:2004
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负责人:Janis J. Weis
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依托单位:
Training Program in Microbial Pathogenesis
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批准号:8663167
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项目类别:
-
资助金额:$24.88万
-
财政年份:2004
-
负责人:Janis J. Weis
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依托单位:
Training Program in Microbial Pathogenesis
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批准号:8461186
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项目类别:
-
资助金额:$27.77万
-
财政年份:2004
-
负责人:Janis J. Weis
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依托单位:
Training Program in Microbial Pathogenesis
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批准号:7940031
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项目类别:
-
资助金额:$26.93万
-
财政年份:2004
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负责人:Janis J. Weis
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依托单位:
Training Program in Microbial Pathogenesis
-
批准号:7272804
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项目类别:
-
资助金额:$25.17万
-
财政年份:2004
-
负责人:Janis J. Weis
-
依托单位:
Training Program in Microbial Pathogenesis
-
批准号:8280380
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项目类别:
-
资助金额:$26.62万
-
财政年份:2004
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负责人:Janis J. Weis
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依托单位:
Training Program in Microbial Pathogenesis
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批准号:7463747
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项目类别:
-
资助金额:$25.19万
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财政年份:2004
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负责人:Janis J. Weis
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依托单位:
Training Program in Microbial Pathogenesis
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批准号:7070084
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项目类别:
-
资助金额:$24.6万
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财政年份:2004
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负责人:Janis J. Weis
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依托单位:
Gordon Conference: Biology of the Spirochetes
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批准号:6664728
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项目类别:
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资助金额:$1.2万
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财政年份:2004
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负责人:Janis J. Weis
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依托单位:
Gordon Conference--Biology of the Spirochetes
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批准号:6358274
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项目类别:
-
资助金额:$1.0万
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财政年份:2002
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负责人:Janis J. Weis
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依托单位:
IDENTIFICATION OF VIRULENCE FACTORS OF BORRELIA BURGDORFERI
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批准号:6245951
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项目类别:
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资助金额:$2.15万
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财政年份:1997
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负责人:Janis J. Weis
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依托单位:
Molecular genetics of Lyme arthritis susceptibility
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批准号:6932332
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项目类别:
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资助金额:$40.62万
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财政年份:1994
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负责人:Janis J. Weis
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依托单位:
Molecular Genetics of Lyme Arthritis Susceptibility
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批准号:7883482
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项目类别:
-
资助金额:$47.47万
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财政年份:1994
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负责人:Janis J. Weis
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依托单位:
Molecular Genetics of Lyme Arthritis
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批准号:8924898
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项目类别:
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资助金额:$32.93万
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财政年份:1994
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负责人:Janis J. Weis
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依托单位:
海外基金