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STAT3 maintains skin barrier integrity by modulating SPINK5 and KLK5 expression in keratinocytes

ABSTRACT: We elucidated the potential role of STAT3 in the skin barrier and its effect on kallikrein-related peptidase 5 (KLK5) and serine protease inhibitor Kazal-type 5 (SPINK5) expression using a mouse model with keratinocyte-specific ablation of STAT3.

ORGANISM(S): Mus musculus

PROVIDER: GSE166140 | GEO | 2021/02/05

REPOSITORIES: GEO

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STAT3 maintains skin barrier integrity by modulating SPINK5 and KLK5 expression in keratinocytes

Project description:STAT3 maintains skin barrier integrity by modulating SPINK5 and KLK5 expression in keratinocytes

| PRJNA699446 | ENA

Human keratinocyte transcriptome response to KLK5 and KLK7

Project description:To determine how KLK5 and KLK7 can impact keratinocyte responses we treated human primary keratinocytes with recombinant KLK5 and KLK7 for 4 hours.

2023-03-01 | GSE205531 | GEO

Comparative analyses of Netherton syndrome patients and Spink5 conditional knock-out mice define disease-relevant pathways

Project description:Netherton syndrome (NS) is a rare skin disease caused by loss-of-function mutations in the serine peptidase inhibitor Kazal type 5 (SPINK5) gene. Disease severity and the lack of efficacious treatments call for a better understanding of NS mechanisms. Here we describe a viable, Spink5 conditional knock-out (cKO) mouse model, allowing to study NS progression. Using comparative transcriptomics and proteomics, we determine a disease molecular profile conserved in mouse models and NS patients. Spink5 cKO mice and NS patients share skin barrier and inflammation signatures defined by up-regulation of proteases, IL-17, IL-36, IL-20 family cytokines. Furthermore, we show that systemic inflammation in Spink5 cKO mice is associated with thymic atrophy and is driven by innate immunity and IL-17/IL-22 signaling. By comparing skin transcriptomes and proteomes, we uncovered several putative substrates of tissue kallikrein-related proteases (KLKs), demonstrating that KLKs can proteolytically regulate IL-36 pro-inflammatory cytokines. Our study thus provides a conserved molecular framework for NS disease, adding new insights into its mechanisms and therapeutic targets.

2023-02-02 | MSV000091184 | MassIVE

Therapeutic effect of anti-KLK5 and KLK7 in a mouse model of atopic dermatitis

Project description:To investigate the effect of blocking the activity of KLK5 and KLK7 in the skin in a model of atopic dermatitis, we treated mice inhibitory antibodies against KLK5 and KLK7.

2023-03-01 | GSE205530 | GEO

Effect of KLK5 knockdown in PC9 lung cancer cells

Project description:Response of PC9 cells to infection with NT (control) lentivirus or one of two different KLK5 knockdown lentiviruses.

2018-04-06 | GSE112783 | GEO

Oral STAT3 Inhibitor, TTI-101, in Patients With Advanced Cancers

Project description:Many patients have cancers that have increased activity of a protein called STAT3 that contributes critically to the development and growth of their cancer. Despite our knowledge of STAT3’s importance to cancer, scientists and doctors have not developed a drug that targets it and that patients can take to treat their cancer more effectively than treatments that are now available. Tvardi Therapeutics, Incorporated has developed a compound, TTI-101, which can be given by mouth and acts as a direct inhibitor of STAT3. Administration of TTI-101 to mice demonstrated that it blocked growth of cancers of the breast, head and neck, lung, and liver and it was safe when administered at high doses to mice, rats, and dogs. In this application, Tvardi is proposing to further develop TTI-101 for treatment of solid tumors for which the prognosis is dismal. The investigators will determine how safe it is when administered to patients with cancer, determine whether an adequate dose can be administered to patients with cancer that will block STAT3 in their cancer, and determine whether treatment with TTI-101 leads to reduced growth of their cancer.

| 2247646 | ecrin-mdr-crc

Effect of KLK5 knockdown in PC9 lung cancer cells

Project description:Effect of KLK5 knockdown in PC9 lung cancer cells

| PRJNA448952 | ENA

Gene expression profile of 22RV1 prostate cancer cells upon SPINK1 knockdown

Project description:Serine Peptidase Inhibitor, Kazal type 1 (SPINK1) overexpression represents the second-largest prostate cancer (PCa) subtype associated with increased risk of biochemical recurrence and poor prognosis. To determine the pathways regulated by SPINK1 in 22RV1 prostate cancer cells, we performed shRNA mediated knockdown of SPINK1 using lentiviral constructs. Scrambled shRNA was used as a control. pGIPZ constructs against SPINK1 (shSPINK1-1, shSPINK1-2, shSPINK1-3) and control shScrambled construct were purchased from Dharmacon.

2019-12-16 | GSE124345 | GEO

NFAT5 Controls the Integrity of Skin II

Project description:The skin protects the human body against dehydration and harmful challenges. Keratinocytes (KCs) are the most frequent epidermal cells, and it is anticipated that KC-mediated transport of Na+ ions creates a physiological barrier of high osmolality against the external environment. We studied in KCs the role of NFAT5, a transcription factor whose activity is controlled by osmotic stress. Cultured KCs from adult mice secrete more than 300 proteins, and upon NFAT5 ablation, the secretion of several matrix proteinases, including metalloproteinase-3 (Mmp3) and kallikrein-related peptidase 7 (Klk7), was markedly enhanced. An increase in Mmp3 and Klk7 RNA levels was also detected in transcriptomes of Nfat5-/- KCs, along with increases of numerous components of ‘Epidermal Differentiation Complex’ (EDC), as proline-rich Sprr and S100 proteins. NFAT5 and Mmp3 are co-expressed in basal KCs from fetal and adult skin but not in skin of newborn mice. This is correlated with a strong increase in Mmp3 and Klk7 expression in KCs of newborn mice and suggests, along with the fragile epidermis of adult Nfat5-/- mice, a suppressive effect of NFAT5 on the expression of matrix proteases in skin. Our data suggest that NFAT5 controls the expression of matrix proteases in skin and contributes to the many fold changes during embryonal skin development and skin integrity in adults.

2021-12-29 | GSE184179 | GEO

NFAT5 Controls the Integrity of Skin I

2021-12-29 | GSE184178 | GEO

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