Investigating How TLR7 Activates and TLR9 Regulates Systemic Autoimmunity
研究 TLR7 如何激活和 TLR9 如何调节系统性自身免疫
基本信息
- 批准号:10327268
- 负责人:
- 金额:$ 45.45万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-05-01 至 2026-04-30
- 项目状态:未结题
- 来源:
- 关键词:AddressAge-MonthsAgonistAnimal ModelAutoantibodiesB-LymphocytesBiochemicalBiologicalBiologyCellsChromatinDNADataDiseaseGeneticGoalsImageInstructionLoxP-flanked alleleLupusMapsMethodsModelingMolecularMusMutant Strains MicePhenotypeProductionPropertyRoleSeriesSignal PathwaySignal TransductionSystemic Lupus ErythematosusTLR7 geneTLR8 geneTestingTherapeutic UsesTissuesWorkage relatedcell typeexperimental studygenetic approachin vivoinsightmacrophagemutantneutrophilnoveloverexpressionrisk variantsystemic autoimmunitytherapeutic evaluation
项目摘要
The long-term goal of the Shlomchik lab is to understand the role of TLRs in SLE. Prior work by us and others
revealed that, surprisingly, disease was markedly exacerbated in the absence of TLR9, even though TLR9
was required for anti-DNA and anti-chromatin autoantibody production. The opposite roles for these two
similar TLRs is likely a fundamental feature of TLR biology and of SLE, yet it is poorly understood. Given the
large number of SLE risk alleles that map to the TLR signaling pathway, we will elucidate this fundamental
biology and how it applies to disease mechanisms and therapy. Experiments proposed in the original
application and which will be continued during the MERIT extension will directly address how TLR7 and TLR9
have divergent roles, how they cross-regulate each other, and how this promotes and regulates disease. Our
lab has pioneered genetic in vivo methods for the study of lupus mechanism in animal models, in part leading
to the recognition of the roles of TLR7 and TLR9, in studies supported in the prior period of this PPG. We
have created novel models and used genetic approaches in order to dissect the cells and molecular signaling
pathways required to promote disease in vivo. In the first three years we have made and analyzed multiple
novel models, which have already greatly informed our insights into how TLR7 and 9 function differently and
control lupus. Additional models are needed, and the mice we have recently made will require substantial in
depth analysis; we must wait 6 months for age-dependent lupus to evolve in these mice. In addition to in vivo
studies, we are now on the verge of determining biochemical and signaling properties of the mutants, which
will provide very novel insights into TLR7 and 9 biology. Our mutant mice allow us to study this in primary B
cells, which our data from Aim 1 shows us are the key cell type. In Aim 1 we will test the hypothesis that
tissue-specific expression of TLR7 and TLR9 explains some or all of their divergent phenotypes. We will use
our new TLR7 floxed mice to examine tissue-specific TLR7 expression to both macrophages and neutrophils
given our recent results that TLR7 expression in B cells is not the whole story. We will also now extend our
studies to TLR8. In Aim 2 we will address the hypothesis that TLR9 regulates TLR7 signals in a cell intrinsic
way. To test this, we are making a series of mutant mice, whose phenotypes need to be determined together
in order to determine how TLR7 and 9 differ and how they cross-regulate. We propose new imaging,
biochemical and cell biological experiments that will illuminate how TR7 vs TLR9 function in primary B cells.
Finally, in Aim 3, we will test the therapeutic potential of TLR inhibition using an inducible Cre to overexpress
TLR9. Last, we will test TLR9 agonists to determine if TLR9 can be used therapeutically to treat disease.
RELEVANCE (See instructions):
Shlomchik实验室的长期目标是了解TLR在SLE中的作用。我们和其他人之前的工作
揭示,令人惊讶的是,在缺乏TLR 9的情况下,疾病明显加重,即使TLR 9
是产生抗DNA和抗染色质自身抗体所必需的。这两个角色的对立
相似TLR可能是TLR生物学和SLE的基本特征,但对其了解甚少。鉴于
大量的SLE危险等位基因映射到TLR信号通路,我们将阐明这一基本
生物学及其如何应用于疾病机制和治疗。原实验中提出的
申请,并将继续在MERIT延长将直接解决如何TLR 7和TLR 9
有不同的作用,它们如何相互交叉调节,以及这如何促进和调节疾病。我们
该实验室开创了在动物模型中研究狼疮机制的体内遗传方法,
在本PPG前期支持的研究中认识到TLR 7和TLR 9的作用。我们
已经创造了新的模型,并使用遗传方法来解剖细胞和分子信号传导,
促进体内疾病所需的途径。在最初的三年里,我们制作并分析了多个
新的模型,这已经大大告知我们的见解TLR 7和9如何不同的功能,
控制狼疮。我们还需要更多的模型,我们最近制造的小鼠需要大量的基因。
深入分析;我们必须等待6个月的年龄依赖性狼疮在这些小鼠中进化。除了在体内
研究,我们现在即将确定突变体的生化和信号特性,
将为TLR 7和TLR 9生物学提供非常新颖的见解。我们的突变小鼠使我们能够在初级B细胞中研究这一点
细胞,我们从Aim 1获得的数据显示,这是关键的细胞类型。在目标1中,我们将检验以下假设:
TLR 7和TLR 9的组织特异性表达解释了它们的部分或全部不同表型。我们将使用
我们的新TLR 7基因敲除小鼠检测了巨噬细胞和中性粒细胞的组织特异性TLR 7表达
鉴于我们最近的结果,即B细胞中的TLR 7表达并不是全部。我们现在也将扩大我们的
研究TLR 8。在目标2中,我们将讨论TLR 9在细胞内调节TLR 7信号的假设。
路上了为了验证这一点,我们正在制造一系列突变小鼠,它们的表型需要一起确定
以确定TLR 7和TLR 9如何不同以及它们如何交叉调节。我们提出了新的成像方法,
生物化学和细胞生物学实验,将阐明TR 7与TLR 9如何在原代B细胞中发挥作用。
最后,在目标3中,我们将测试TLR抑制的治疗潜力,使用诱导型Cre过表达
TLR9。最后,我们将测试TLR 9激动剂,以确定TLR 9是否可以用于治疗疾病。
相关性(参见说明):
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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MARK J SHLOMCHIK其他文献
MARK J SHLOMCHIK的其他文献
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{{ truncateString('MARK J SHLOMCHIK', 18)}}的其他基金
Investigating How TLR7 Activates and TLR9 Regulates Systemic Autoimmunity
研究 TLR7 如何激活和 TLR9 如何调节系统性自身免疫
- 批准号:
10598477 - 财政年份:2021
- 资助金额:
$ 45.45万 - 项目类别:
Investigating How TLR7 Activates and TLR9 Regulates Systemic Autoimmunity
研究 TLR7 如何激活和 TLR9 如何调节系统性自身免疫
- 批准号:
10049283 - 财政年份:2021
- 资助金额:
$ 45.45万 - 项目类别:
Exploring the Role of Long Noncoding RNAs in Germinal Center B cells
探索长非编码 RNA 在生发中心 B 细胞中的作用
- 批准号:
10154493 - 财政年份:2020
- 资助金额:
$ 45.45万 - 项目类别:
Exploring the Role of Long Noncoding RNAs in Germinal Center B cells
探索长非编码 RNA 在生发中心 B 细胞中的作用
- 批准号:
10308111 - 财政年份:2020
- 资助金额:
$ 45.45万 - 项目类别:
Investigating the Repertoires and Functions of T Cells that Help Autoreactive B Cells in Lupus
研究帮助狼疮中自身反应性 B 细胞的 T 细胞的组成和功能
- 批准号:
10058242 - 财政年份:2017
- 资助金额:
$ 45.45万 - 项目类别:
Investigating the Repertoires and Functions of T Cells that Help Autoreactive B Cells in Lupus
研究帮助狼疮中自身反应性 B 细胞的 T 细胞的组成和功能
- 批准号:
10308077 - 财政年份:2017
- 资助金额:
$ 45.45万 - 项目类别:
Investigating How TLR7 Activates and TLR9 Regulates Systemic Autoimmunity
研究 TLR7 如何激活和 TLR9 如何调节系统性自身免疫
- 批准号:
9175268 - 财政年份:2016
- 资助金额:
$ 45.45万 - 项目类别:
Investigating How TLR7 Activates and TLR9 Regulates Systemic Autoimmunity
研究 TLR7 如何激活和 TLR9 如何调节系统性自身免疫
- 批准号:
9273442 - 财政年份:2016
- 资助金额:
$ 45.45万 - 项目类别:
Investigating How TLR7 Activates and TLR9 Regulates Systemic Autoimmunity
研究 TLR7 如何激活和 TLR9 如何调节系统性自身免疫
- 批准号:
9917691 - 财政年份:2016
- 资助金额:
$ 45.45万 - 项目类别:
Signaling and Selection in Germinal Center B Cells
生发中心 B 细胞的信号传导和选择
- 批准号:
9017907 - 财政年份:2014
- 资助金额:
$ 45.45万 - 项目类别: