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
• 负责人: Joanne Michelle Kahlenberg
• 金额: $ 49.61万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/10675692
• 关键词: Address; Apical; Apoptosis; Apoptotic; Automobile Driving; Behavior; Biology; CASP3 gene; CASP8 gene; Cells; Characteristics; Chromatin; Chronic; Cutaneous Lupus Erythematosus; Data; Disease; Exhibits; FOXO1A gene; FOXO3A gene; Flare; Fostering; Functional disorder; Genetic; Genetic Transcription; Goals; IRF3 gene; Inflammation; Inflammatory Response; Interferon Type I; Interferons; Knowledge; LATS1 gene; Lesion; Literature; Lupus; Malignant Neoplasms; Mediating; Mediator; Mission; Nucleic Acids; Organ; Pathogenicity; Pathologic; Pathway interactions; Patients; Phosphorylation; Phosphotransferases; Photosensitivity; Prevention; Production; Proteins; Public Health; Reporting; Research; Risk; Role; Secondary to; Signal Pathway; Signal Transduction; Skin; Stimulator of Interferon Genes; Systemic Lupus Erythematosus; TBK1 gene; TRAF6 gene; Therapeutic; Ubiquitination; Ultraviolet B Radiation; United States National Institutes of Health; Up-Regulation; Virus Diseases; Work; barrier to care; chemokine; cytokine; disability; improved; in vivo; in vivo Model; inflammatory modulation; inhibitor; keratinocyte; kinase inhibitor; lupus cutaneous; member; novel; novel therapeutics; overexpression; prevent; response; side effect; skin disorder; synergism

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.

项目摘要/摘要 全身性红斑狼疮（SLE）患者的非静态和病变的皮肤富含I型干扰素 （IFN）有助于感染，凋亡和光敏性的承诺。重要的是，虽然是新的 现在，药物已被批准用于全球对SLE中I型IFN信号的封锁，其影响可能是中等的，并且 副作用，包括病毒感染的风险，仍然是治疗的障碍。此外，干扰素是 重要的是，关于如何规范干扰素生产的承诺和 SLE皮肤炎症。解决这一差距将导致对CLE病变的机械理解 针对精确消除没有副作用的病原体，例如全球产生的病原体 IFN封锁，并有可能预防疾病。我们的新型初步数据已经发现了功能的作用 通过顶部钥匙的过表达，SLE角质形成细胞中河马信号通路的失调 调节器，含有蛋白质1（WWC1）的WW结构域，导致河马信号传导和 与是相关蛋白（YAP）的磷酸化增加。我们的数据还表明，yap的偏见 磷酸化对于在SLE中鉴定出的异常凋亡反应可能至关重要 角质形成细胞。虽然这些数据自行影响，但癌症文献的最新报道也表明 河马途径的成员可能是通过与 CGA/Sting Pathway5,6。实际上，我们的初步数据将IFN-κ的SLE超过生产识别为sting- 通过LATS1/2的抑制作用的依赖和阻断YAP磷酸化，足以阻止IFNK 激活后转录。这些数据构成了我们整体假设的基础，即失调 河马信号传导是狼疮性角质形成症功能障碍的关键驱动力，并且调节键的河马 - 信号传导介质将“正常化”角质形成细胞行为。我们将通过 以下目的：目标1：揭示河马途径在驱动增强的SLE角质形成细胞中的作用 凋亡。目标2：确定河马信号偏向I型产生的机制 SLE角质形成细胞中的干扰素。 AIM 3：确定河马信号在UVB介导的NF-κB-中的作用 驱动的炎症反应。成功完成该建议将揭示重要的新生物学 涉及I型IFN和HIPPO信号的相互作用，并识别特定的河马途径目标 充当预防和治疗SLE皮肤病的新目标。