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/文摘
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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