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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：
Joanne Michelle Kahlenberg
金额：
$ 46.68万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
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：
https://reporter.nih.gov/project-details/10536347
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 Lead Lesion Literature Lupus Malignant Neoplasms Mediating Mediator of activation protein 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 inhibitor keratinocyte kinase inhibitor lupus cutaneous member novel novel therapeutics overexpression prevent response side effect skin disorder skin 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