Conformational regulation of TGF-β activation by integrin αvβ6
整合素 αvβ6 对 TGF-β 激活的构象调节
基本信息
- 批准号:10655988
- 负责人:
- 金额:$ 79.97万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-07-01 至 2027-06-30
- 项目状态:未结题
- 来源:
- 关键词:AddressApicalBindingBinding ProteinsBiologicalBiological AssayCell surfaceCellsClinicalComplexCryoelectron MicroscopyCrystallographyDataDevelopmentDiffuseDiffusionEventExtracellular MatrixFibrosisGene DeletionGoalsHeadHomeostasisHumanImmuneInflammatoryIntegrinsLRRC32 geneLengthLigand BindingLung diseasesMediatingMediatorMedicalMembraneMethodsModelingMolecular ConformationMonoclonal AntibodiesPathologicPathologyPeptidesPharmaceutical PreparationsPhase II Clinical TrialsPhysiologicalPlayPre-Clinical ModelPrimatesPropertyProteinsPulmonary FibrosisRegulationResearchResolutionRiskRodentRoleSafetySeriesSignal InductionSignal TransductionStructureTechniquesTestingTherapeuticToxic effectTransforming Growth Factor betaTransforming Growth Factor beta ReceptorsTransforming Growth FactorsVisualizationchronic inflammatory lung diseaseconformational conversioncytokinedesigneffective therapyidiopathic pulmonary fibrosisimprovedin vivoinsightlatent TGF-beta binding proteinparticleprotein complexreceptortherapeutic targettherapy development
项目摘要
Summary/Abstract: TGF-b is a key driver of lung fibrosis. The long-term goal of our research is to acquire a
deep understanding of the regulation of TGF-b activity to develop new strategies and treatments for fibrosing
lung disease. Currently, there are no effective therapies to treat lung fibrosis. The multifunctional cytokine TGF-
b is a potent mediator of fibrosis and is a potential therapeutic target in fibrosing lung disease. However,
targeting TGF-b itself or its receptors is associated with demonstrated risks as evidenced by toxicities in
rodents, primates and humans. More selective targeting of the fibroinflammatory effects of TGF-b, without
perturbing its normal essential functions are highly desirable. One property of TGF-b that may allow more
selective targeting is to target its “activation” since it is always produced in a latent form (L-TGF-b) that requires
activation in order to function. Another feature of L-TGF-b that could facilitate more specific targeting is to that
it is normally covalently bound to the extracellular matrix or to the surface of cells by association with TGF-b
binding proteins such as latent-TGF-b binding protein (LTBP) or glycoprotein-A repetitions predominant
(GARP). We and others have shown that L-TGF-b binding to two integrins, a 8 and a
vb
vb
6 is essential for
TGF-b activation in vivo. For the integrin a 6 activation mechanism, it has long been assumed that TGF-b
vb
must be released from LAP so that free TGF-b can diffuse and bind its receptors on target cells. The structural
mechanism for such release of TGF-b is incompletely understood since full-length a
vb
6 has not been studied
in complex with TGF-b bound to TGF-b binding proteins. Based on recent structural data obtained using single
particle electron cryomicroscopy (cryo-EM), we have recently proposed a new model whereby a
vb
8 can bind
to L-TGF-b on cells presenting the L-TGF-b/GARP complex and induce signaling without release and diffusion
of TGF-b. These two different models of TGF-b activation may be able to be separately targeted, which could
help mitigate therapeutic risk. Here in four aims, we will employ a structure-based approach to address the
mechanism of a
vb
6-mediated TGF-b activation. We will use the technique of electron cryomicroscopy (cryo-
EM), which is a technique that allows for high-resolution structures of proteins and protein complexes in
physiologically relevant conditions. Cryo-EM will be used to examine the role of integrin a
vb
6 conformation in
the mechanism of TGF-b activation. These studies will improve mechanistic understanding of TGF-b activation
and therapeutic targeting strategies to more selectively and safely inhibit it.
摘要/摘要:TGF-B是肺纤维化的关键驱动力。我们研究的长期目标是获得
对TGF-B活动的调节,以开发新的策略和治疗方法
肺部病。目前,尚无治疗肺纤维化的有效疗法。多功能细胞因子TGF-
B是纤维化的潜在介体,是纤维化肺部疾病的潜在治疗靶标。然而,
针对TGF-B本身或其接收器与表现出的风险相关
啮齿动物,私人和人类。更具选择性的靶向TGF-B的纤维炎症效应,没有
扰动其正常的基本功能是非常可取的。 TGF-B的一个属性可能允许更多
选择性定位是针对其“激活”,因为它始终以潜在形式(L-TGF-B)产生
激活以发挥作用。 L-TGF-B的另一个功能可以促进更具体的定位
它通常通过与TGF-B的结合而共价结合到细胞外基质或细胞表面
结合蛋白,例如潜在-TGF-B结合蛋白(LTBP)或糖蛋白A-A重复蛋白
(GARP)。我们和其他其他
VB
VB
6对于
体内TGF-B激活。对于整联蛋白A 6激活机制,长期以来一直认为TGF-B
VB
必须从膝盖中释放出来,以便游离TGF-B可以扩散并结合其在目标细胞上的接收器。结构
由于全长A
VB
6尚未研究
与TGF-B结合到TGF-B结合蛋白的复合物。基于最新的结构数据,使用了单个
颗粒电子冷冻显微镜(冷冻EM),我们最近提出了一个新模型
VB
8可以结合
在呈现L-TGF-B/GARP复合物的细胞上的L-TGF-B,并诱导信号传导而无需释放和扩散
TGF-B。这两种不同的TGF-B激活模型可能能够分别针对
帮助减轻治疗风险。在四个目标中,我们将采用一种基于结构的方法来解决
a的机制
VB
6介导的TGF-B激活。我们将使用电子冷冻显微镜技术(冷冻 -
em),这是一种允许在蛋白质和蛋白质复合物中的高分辨率结构的技术
生理上相关的条件。冷冻EM将用于检查整联蛋白的作用
VB
6构象
TGF-B激活的机制。这些研究将提高对TGF-B激活的机械理解
以及治疗性靶向策略,以更有选择性,安全地抑制它。
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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Yifan Cheng其他文献
Yifan Cheng的其他文献
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{{ truncateString('Yifan Cheng', 18)}}的其他基金
Advancing cryo-EM technology to address difficult biological questions
推进冷冻电镜技术解决棘手的生物学问题
- 批准号:
10570241 - 财政年份:2021
- 资助金额:
$ 79.97万 - 项目类别:
Advancing cryo-EM technology to address difficult biological questions
推进冷冻电镜技术解决棘手的生物学问题
- 批准号:
10166355 - 财政年份:2021
- 资助金额:
$ 79.97万 - 项目类别:
Advancing cryo-EM technology to address difficult biological questions
推进冷冻电镜技术解决棘手的生物学问题
- 批准号:
10376252 - 财政年份:2021
- 资助金额:
$ 79.97万 - 项目类别:
Structural mechanism of integrin-mediated TGF-b activation
整合素介导的TGF-b激活的结构机制
- 批准号:
10171882 - 财政年份:2016
- 资助金额:
$ 79.97万 - 项目类别:
Structural mechanism of integrin-mediated TGF-b activation
整合素介导的TGF-b激活的结构机制
- 批准号:
10615758 - 财政年份:2016
- 资助金额:
$ 79.97万 - 项目类别:
Structural mechanism of integrin-mediated TGF-b activation
整合素介导的TGF-b激活的结构机制
- 批准号:
10407522 - 财政年份:2016
- 资助金额:
$ 79.97万 - 项目类别:
Structures and gating mechanisms of TRP ion channels
TRP离子通道的结构和门控机制
- 批准号:
9149283 - 财政年份:2011
- 资助金额:
$ 79.97万 - 项目类别:
Determine high-resolution structure of membrane protein by single particle cryoEM
通过单颗粒冷冻电镜确定膜蛋白的高分辨率结构
- 批准号:
8513370 - 财政年份:2011
- 资助金额:
$ 79.97万 - 项目类别:
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