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Drug Repurposing Using Molecular Network Analysis Identifies Janus Kinase as Targetable Driver in Necrobiosis Lipoidica

ABSTRACT: Drug Repurposing Using Molecular Network Analysis Identifies Janus Kinase as Targetable Driver in Necrobiosis Lipoidica

PROVIDER: PRJNA1109817 | ENA |

REPOSITORIES: ENA

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Drug Repurposing Using Molecular Network Analysis Identifies Janus Kinase as Targetable Driver in Necrobiosis Lipoidica

Project description:Drug repurposing is an attractive strategy for therapy development, particularly in rare diseases where traditional drug development approaches may be challenging due to high cost and small numbers of patients. Here we used a novel drug identification and repurposing pipeline to identify candidate targetable drivers of disease and corresponding therapies through application of causal reasoning using a combination of open-access resources and transcriptomics data. We optimized our approach on psoriasis as a disease model, demonstrating the ability to identify known and novel molecular drivers of psoriasis and link them to current and emerging therapies. Application of our approach to a cohort of tissue samples of necrobiosis lipoidica, an unrelated, rare, and to date molecularly poorly characterized cutaneous inflammatory disorder, identified a unique set of upstream regulators, particularly highlighting the role of IFNG and the JAK-STAT pathway as a likely driver of disease pathogenesis and linked it to JAK inhibitors as potential therapy. Analysis of an independent cohort of NL samples validated these findings with the overall agreement of drug matched upstream regulators above 96%. These data highlight utility of our approach in rare diseases and offer a novel opportunity for drug discovery in other rare diseases in dermatology and beyond.

2024-05-15 | GSE267132 | GEO

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Janus nanoparticles targeting extracellular polymeric substance achieve flexible elimination of drug-resistant biofilms

Project description:Safe and efficient antibacterial materials are urgently needed to combat drug-resistant bacteria and biofilm-associated infections. The rational design of nanoparticles for flexible elimination of biofilms by alternative strategies remains challenging. Herein, we propose the fabrication of Janus-structured nanoparticles targeting extracellular polymeric substance to achieve dispersion or near-infrared (NIR) light-activated photothermal elimination of drug-resistant biofilms, respectively. Asymmetrical Janus-structured dextran-bismuth selenide (Dex-BSe) nanoparticles are fabricated by a facile strategy to exploit synergistic effects of both components. The biocompatible dextran domain with the maximum exposure endows the Janus nanoparticles with biofilm penetration, targeting, and dispersion functions. Interestingly, Janus Dex-BSe nanoparticles realize enhanced dispersal of biofilms over time compared with dextran nanoparticles while the underlying molecular mechanisms are further revealed by RNA-sequencing transcriptomics analysis. Alternatively, taking advantage of the preferential accumulation of nanoparticles at infection sites, the self-propelled active motion induced by the unique Janus structure enhances the photothermal killing effect under NIR light irradiation, thereby eradicating the biofilm. Given these favorable features, the antibiofilm activity of Janus Dex-BSe against methicillin-resistant Staphylococcus aureus (MRSA) was first validated in vitro. More importantly, the flexible application of Janus Dex-BSe nanoparticles for biofilm removal or NIR-triggered eradication in vivo was demonstrated by MRSA-infected mouse excisional wound model and abscess model, respectively. The currently developed Janus nanoplatform holds great promise for the efficient elimination of drug-resistant biofilms in diverse antibacterial scenarios.

2023-08-01 | GSE239411 | GEO

Stromal inflammation is a targetable driver of hematopoietic aging [Microarray analysis]

Project description:Stromal inflammation is a targetable driver of hematopoietic aging [Microarray analysis]

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Machine Learning Identifies Candidates for Drug Repurposing in Alzheimer's Disease

Project description:Clinical trials of novel therapeutics for Alzheimer's Disease (AD) have consumed a large amount of time and resources with largely negative results. Repurposing drugs already approved by the Food and Drug Administration (FDA) for another indication is a more rapid and less expensive option. In this study, we profile 80 FDA-approved and clinically tested drugs in neural cell cultures, with the goal of producing a ranked list of possible repurposing candidates.

2021-01-14 | GSE164788 | GEO

Stromal inflammation is a targetable driver of hematopoietic aging [droplet-based scRNAseq]

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Janus kinase-Inhibition modulates hepatitis E virus infection

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Janus kinase 1 plays a critical role in mammary cancer progression

Project description:Janus kinases (JAKs) and their downstream STAT proteins play key roles in cytokine signaling, tissue homeostasis, and cancer development. Using a novel breast cancer model that conditionally lacks the Janus kinase 1, we show here that JAK1 is essential for IL-6 class inflammatory cytokine signaling and plays a critical role in metastatic cancer progression. JAK1 is indispensable for the oncogenic activation of STAT1, STAT3, and STAT6 in ERBB2-expressing cancer cells, suggesting that ERBB2 receptor tyrosine kinase complexes do not directly activate these STAT proteins in vivo. A genome-wide gene expression analysis revealed that JAK1 signaling has pleiotropic effects on several pathways associated with cancer progression. We established that FOS and MAP3K8 are targets of JAK1/STAT3 signaling that promote tumorsphere formation and cell migration. The results highlight the significance of JAK1 as a rational therapeutic target to block IL-6 class cytokines that are master regulators of cancer-associated inflammation.

2019-03-27 | GSE121064 | GEO

Dysregulated RPB1 is a targetable master driver of overgrowth in acute myeloid leukemia.

Project description:Dysregulated RPB1 is a targetable master driver of overgrowth in acute myeloid leukemia.

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