alpha v integrin regulation of B cell tolerance
B 细胞耐受的 α v 整合素调节
基本信息
- 批准号:10294130
- 负责人:
- 金额:$ 20万
- 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
- 起止时间:2020-12-16 至 2021-11-30
- 项目状态:已结题
- 来源:
- 关键词:AffectAffinityAmericanAnimal ModelAntigensApoptoticAutoantibodiesAutoantigensAutoimmuneAutoimmune DiseasesAutoimmune ResponsesAutoimmunityAutophagocytosisB cell differentiationB-Cell ActivationB-Cell DevelopmentB-LymphocytesCD19 geneCell DeathCell ProliferationCellsChronicComplexDNADataDevelopmentEndosomesEtiologyExcisionExposure toFrequenciesGeneticGoalsGrantHomologous GeneImmune ToleranceImmune responseImmune signalingImmune systemImmunoglobulin Class SwitchingInflammationInflammatoryIntegrin alphaVIntegrinsInterferon-betaInterferonsKidneyKnock-outKnockout MiceLigandsLinkMediatingMissionModelingMouse StrainsMusNucleic AcidsOrganPathway interactionsPatientsPattern recognition receptorPeripheralPlasma CellsProductionRNAReceptor SignalingRegulationRegulatory PathwayResearchRheumatoid ArthritisRoleSignal TransductionSkinSystemic Lupus ErythematosusTestingToll-like receptorsTransgenic MiceTranslatingUnited States National Institutes of HealthWorkautoreactive B cellautoreactivitybasechronic inflammatory diseasedesignexperimental studyimmunoregulationin vivoinnovationinsightlupus-likemouse modelnovelnovel therapeutic interventionperipheral tolerancerecruitresponsetrafficking
项目摘要
PROJECT SUMMARY
There is a fundamental need to understand how the immune system discriminates self-antigens and regulates
potentially harmful autoimmune responses. Increasing evidence from genetics and functional studies indicate
that innate immune signaling in response to products caused by cell death is a major etiological factor in
autoimmune and chronic inflammatory disease. Our long-term goal is to better understand how immune
tolerance to antigens derived from apoptotic cells and other self-antigens is maintained and how this can break
down in autoimmune diseases. The objective in this application is to understand how av integrins and
components of the autophagy pathway contribute to B cell tolerance. Our central hypothesis is that av-
mediated activation of autophagy components regulates TLR signaling in B cells, limiting cell proliferation,
differentiation and production of autoantibodies. The rationale for this grant is that the proposed work will
define the role of av-mediated autophagy in B cell tolerance, and develop better models for autoimmune
disease. Furthermore, this work has the potential to translate into new therapeutic approaches through the use
of existing compounds that target av and autophagy. Based on strong preliminary data, our hypothesis will be
tested in three specific aims: (1) Determine how av regulates development of autoreactive B cells and lupus-
like autoimmunity in mice. av-knockout mice crossed with an autoreactive BCR heavy chain transgenic mouse
strain will be used to follow development of autoreactive B cells, and understand how av regulates tolerance
and response to self-antigen. (2) Determine how av-mediated regulation of type I-IFNs regulates B cell
tolerance. We will test how increased type I IFN production by B cells and plasmacyotid DCs contribute to B
cell activation. (3) Test the hypothesis that non-canonical autophagy regulates B cell TLR signaling to promote
tolerance. We will analyze the role of Rubicon in autoreactive B cell activation, and evaluate a potential new
component of non-canonical autophagy, Atg16l2 Our approach is innovative as it focuses on a novel role for
integrins and autophagy components in regulating immune signaling in B cells. The proposed work is
significant because it will establish a new paradigm for B cell recognition of potential self-antigens in immune
tolerance and provide a mechanism by which this occurs. Ultimately this has the potential to change our
understanding of how immune tolerance is maintained and how autoreactive B cells may escape control to
promote autoimmunity.
项目摘要
有一个基本的需要了解免疫系统如何区分自身抗原和调节
潜在有害的自身免疫反应。越来越多的遗传学和功能研究证据表明,
先天免疫信号对细胞死亡引起的产物的反应是免疫缺陷的主要致病因素。
自身免疫性和慢性炎症性疾病。我们的长期目标是更好地了解免疫
对来自凋亡细胞和其他自身抗原的抗原的耐受性得以维持,以及这种耐受性如何破坏
降低自身免疫性疾病的发病率本申请的目的是了解av整联蛋白和
自噬途径的组分有助于B细胞耐受性。我们的中心假设是,
介导的自噬组分的活化调节B细胞中的TLR信号传导,限制细胞增殖,
分化和自身抗体的产生。这项赠款的理由是,拟议的工作将
确定av介导的自噬在B细胞耐受中的作用,并开发更好的自身免疫模型
疾病此外,这项工作有可能通过使用
针对AV和自噬的现有化合物。基于强有力的初步数据,我们的假设将是
在三个特定目标中进行测试:(1)确定av如何调节自身反应性B细胞和狼疮的发展-
比如小鼠的自身免疫。av基因敲除小鼠与自身反应性BCR重链转基因小鼠杂交
菌株将用于跟踪自身反应性B细胞发育,并了解av如何调节耐受性
和对自身抗原的反应(2)确定av介导的I型干扰素调节如何调节B细胞
宽容我们将测试B细胞和浆细胞DC增加的I型IFN产生如何对B产生贡献
细胞激活(3)检验非经典自噬调节B细胞TLR信号传导以促进
宽容我们将分析Rubicon在自身反应性B细胞活化中的作用,并评估一种潜在的新的
我们的方法是创新的,因为它专注于一个新的作用,
整合素和自噬组分在调节B细胞中的免疫信号传导中的作用。拟议的工作是
意义重大,因为它将建立免疫中B细胞识别潜在自身抗原的新范例
容忍并提供一种机制,通过这种机制发生。最终,这有可能改变我们的
了解免疫耐受是如何维持的,以及自身反应性B细胞如何逃脱控制,
促进自身免疫。
项目成果
期刊论文数量(0)
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会议论文数量(0)
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Adam Lacy-Hulbert其他文献
Adam Lacy-Hulbert的其他文献
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{{ truncateString('Adam Lacy-Hulbert', 18)}}的其他基金
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LITAF 调节细胞死亡和炎症反应
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使用转座子诱变鉴定流感宿主药物开发靶点
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9089858 - 财政年份:2015
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8883359 - 财政年份:2014
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Transposon Mutagenesis for Host-Target and Drug Discovery in Infectious Disease
传染病宿主靶标和药物发现的转座子诱变
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Dendritic Cell Control of Intestinal T Cell Responses
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8868105 - 财政年份:2012
- 资助金额:
$ 20万 - 项目类别:
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树突状细胞控制肠道 T 细胞反应
- 批准号:
8372489 - 财政年份:2012
- 资助金额:
$ 20万 - 项目类别:
Transposon Mutagenesis for Host-Target and Drug Discovery in Infectious Disease
传染病宿主靶标和药物发现的转座子诱变
- 批准号:
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$ 20万 - 项目类别:
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- 批准号:
8843114 - 财政年份:2012
- 资助金额:
$ 20万 - 项目类别:
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