Hippo signaling as a critical regulator of lupus keratinocyte dysfunction
Hippo 信号作为狼疮角质形成细胞功能障碍的关键调节因子
基本信息
- 批准号:10536347
- 负责人:
- 金额:$ 46.68万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-08-02 至 2027-05-31
- 项目状态:未结题
- 来源:
- 关键词:AddressApicalApoptosisApoptoticAutomobile DrivingBehaviorBiologyCASP3 geneCASP8 geneCellsCharacteristicsChromatinChronicCutaneous Lupus ErythematosusDataDiseaseExhibitsFOXO1A geneFOXO3A geneFlareFosteringFunctional disorderGeneticGenetic TranscriptionGoalsIRF3 geneInflammationInflammatory ResponseInterferon Type IInterferonsKnowledgeLATS1 geneLeadLesionLiteratureLupusMalignant NeoplasmsMediatingMediator of activation proteinMissionNucleic AcidsOrganPathogenicityPathologicPathway interactionsPatientsPhosphorylationPhosphotransferasesPhotosensitivityPreventionProductionProteinsPublic HealthReportingResearchRiskRoleSecondary toSignal PathwaySignal TransductionSkinStimulator of Interferon GenesSystemic Lupus ErythematosusTBK1 geneTRAF6 geneTherapeuticUbiquitinationUltraviolet B RadiationUnited States National Institutes of HealthUp-RegulationVirus DiseasesWorkbarrier to carechemokinecytokinedisabilityimprovedin vivoin vivo Modelinhibitorkeratinocytekinase inhibitorlupus cutaneousmembernovelnovel therapeuticsoverexpressionpreventresponseside effectskin disorderskin lesion
项目摘要
PROJECT SUMMARY/ABSTRACT
The non-lesional and lesional skin of systemic lupus erythematosus (SLE) patients is rich in type I interferons
(IFNs) which contribute to a propensity for inflammation, apoptosis, and photosensitivity. Importantly, while new
drugs are now approved for global blockade of type I IFN signaling in SLE, their effects may be moderate and
side effects, including risk of viral infections, remain a barrier to treatment. Further, while interferons are
important, there is a critical knowledge gap as to what regulates the propensity for interferon production and
inflammation in SLE skin. Addressing this gap will lead to mechanistic understanding of CLE lesions that can be
targeted to precisely eliminate the pathogenic players without side effects, such as those generated by global
IFN blockade, and potentially prevent disease. Our novel preliminary data has uncovered a role for functional
dysregulation of the Hippo signaling pathway in SLE keratinocytes through overexpression of the apical key
regulator, WW domain containing protein 1 (WWC1), resulting in chronic overactivation of Hippo signaling and
increased phosphorylation of Yes-associated protein (YAP). Our data also show that this skewing of YAP
phosphorylation may be critical for the aberrant apoptotic responses that have been identified in SLE
keratinocytes. While this data is impactful on its own, recent reports in the cancer literature also suggest that
members of the Hippo pathway may be critical regulators of type I IFN production through interactions with the
cGAS/STING pathway5,6. Indeed, our preliminary data identify SLE-overproduction of IFN-κ as STING-
dependent and blockade of YAP phosphorylation through LATS1/2 inhibition as sufficient to block IFNK
transcription after STING activation. These data form the basis of our overall hypothesis that dysregulation
of Hippo signaling is a critical driver of lupus keratinocyte dysfunction and that modulation of key Hippo-
signaling mediators will “normalize” lupus keratinocyte behavior. We will address this hypothesis through
the following aims: Aim 1: Uncover the role of the Hippo pathway in driving enhanced SLE keratinocyte
apoptosis. Aim 2: Determine the mechanisms by which Hippo signaling skews the production of type I
interferons in SLE keratinocytes. Aim 3: Determine the role of Hippo signaling in UVB-mediated NF-κB-
driven inflammatory responses. Successful completion of this proposal will uncover important new biology
regarding the interaction of type I IFNs and Hippo signaling and identify specific Hippo pathway targets that will
serve as novel targets for prevention and treatment of SLE skin disease.
项目总结/摘要
系统性红斑狼疮(SLE)患者的非皮损和皮损皮肤富含I型干扰素
干扰素(IFN),其有助于炎症、凋亡和光敏性的倾向。重要的是,虽然新
目前已批准药物用于全面阻断SLE中I型IFN信号传导,它们的作用可能是中等的,
包括病毒感染风险在内的副作用仍然是治疗的障碍。此外,虽然干扰素是
重要的是,关于什么调节干扰素产生的倾向,
SLE皮肤炎症。解决这一差距将导致对CLE病变的机械理解,
有针对性地精确消除致病因素,而没有副作用,例如全球性的
干扰素阻断,并可能预防疾病。我们新的初步数据揭示了功能性
通过顶端关键蛋白的过表达导致SLE角质形成细胞中Hippo信号通路失调
调节因子,含WW结构域的蛋白1(WWC 1),导致Hippo信号传导的慢性过度活化,
增加的Yes相关蛋白(雅普)磷酸化。我们的数据还表明,这种倾斜的雅普,
磷酸化可能是SLE中已确定的异常凋亡反应的关键
角质形成细胞虽然这些数据本身就很有影响力,但最近的癌症文献报告也表明,
Hippo途径的成员可能是I型IFN产生的关键调节剂,通过与IFN-γ的相互作用,
cGAS/STING途径5,6.事实上,我们的初步数据将SLE-IFN-κ的过度生产确定为STING-1。
通过LATS 1/2抑制作用依赖和阻断雅普磷酸化,足以阻断IFNK
STING激活后的转录。这些数据构成了我们总体假设的基础,即失调
是狼疮角质形成细胞功能障碍的关键驱动因素,
信号传导介质将使狼疮角质形成细胞行为“正常化”。我们将通过以下方式来解决这一假设:
目的1:揭示Hippo通路在驱动增强的SLE角质形成细胞中的作用
凋亡目的2:确定Hippo信号传导扭曲I型胶原蛋白产生的机制。
SLE角质形成细胞中的干扰素。目的3:探讨Hippo信号通路在UVB介导的NF-κB-κB损伤中的作用。
引发炎症反应。成功完成这项提案将揭示重要的新生物学
关于I型IFN和Hippo信号传导的相互作用,并确定特定的Hippo通路靶标,
作为预防和治疗SLE皮肤病的新靶点。
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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Joanne Michelle Kahlenberg其他文献
Joanne Michelle Kahlenberg的其他文献
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{{ truncateString('Joanne Michelle Kahlenberg', 18)}}的其他基金
Hippo signaling as a critical regulator of lupus keratinocyte dysfunction
Hippo 信号作为狼疮角质形成细胞功能障碍的关键调节因子
- 批准号:
10675692 - 财政年份:2022
- 资助金额:
$ 46.68万 - 项目类别:
Linking Disease Mechanisms and Outcomes in Rheumatic Diseases
将风湿性疾病的疾病机制和结果联系起来
- 批准号:
10657643 - 财政年份:2020
- 资助金额:
$ 46.68万 - 项目类别:
Linking Disease Mechanisms and Outcomes in Rheumatic Diseases
将风湿性疾病的疾病机制和结果联系起来
- 批准号:
10210191 - 财政年份:2020
- 资助金额:
$ 46.68万 - 项目类别:
Linking Disease Mechanisms and Outcomes in Rheumatic Diseases
将风湿性疾病的疾病机制和结果联系起来
- 批准号:
10447037 - 财政年份:2020
- 资助金额:
$ 46.68万 - 项目类别:
Characterization of Interferon Kappa as a Novel Target in Cutaneous Lupus
干扰素 Kappa 作为皮肤狼疮新靶点的表征
- 批准号:
9761987 - 财政年份:2017
- 资助金额:
$ 46.68万 - 项目类别:
Characterization of Interferon Kappa as a Novel Target in Cutaneous Lupus
干扰素 Kappa 作为皮肤狼疮新靶点的表征
- 批准号:
10238899 - 财政年份:2017
- 资助金额:
$ 46.68万 - 项目类别:
Characterization of Interferon Kappa as a Novel Target in Cutaneous Lupus
干扰素 Kappa 作为皮肤狼疮新靶点的表征
- 批准号:
10470213 - 财政年份:2017
- 资助金额:
$ 46.68万 - 项目类别:
Characterization of Interferon Kappa as a Novel Target in Cutaneous Lupus
干扰素 Kappa 作为皮肤狼疮新靶点的表征
- 批准号:
10004499 - 财政年份:2017
- 资助金额:
$ 46.68万 - 项目类别:
Identification of BATF2 as a Regulator of Interferon-Enhanced Inflammatory Responses in Lupus Skin
鉴定 BATF2 作为狼疮皮肤中干扰素增强炎症反应的调节剂
- 批准号:
9375222 - 财政年份:2017
- 资助金额:
$ 46.68万 - 项目类别:
Understanding transcriptional connections between cutaneous and systemic lupus
了解皮肤狼疮和系统性狼疮之间的转录联系
- 批准号:
8825016 - 财政年份:2014
- 资助金额:
$ 46.68万 - 项目类别:
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