Project description:Acute kidney injury frequently occurs in patients with severe pneumonia and contributes to poor clinical outcomes. In this study, we established a mouse model of severe pneumonia–associated acute kidney injury (SP-AKI) and performed RNA sequencing to investigate transcriptomic alterations in both lung and kidney tissues. Lung and kidney samples were collected from control mice and SP-AKI mice, followed by high-throughput RNA sequencing. Differential gene expression and pathway analyses were performed to identify molecular mechanisms involved in organ injury and inter-organ communication during SP-AKI. This dataset provides a comprehensive transcriptomic resource for understanding the molecular mechanisms underlying SP-AKI.
Project description:The intermediate filament protein Nestin serves as a biomarker for stem cells and has been used to identify subsets of cancer stem-like cells. However, the mechanistic contributions of Nestin to cancer pathogenesis are not understood. Here we report that Nestin binds the hedgehog pathway transcription factor Gli3 to mediate the development of medulloblastomas of the hedgehog subtype. In a mouse model system, Nestin levels increased progressively during medulloblastoma formation resulting in enhanced tumor growth. Conversely, loss of Nestin dramatically inhibited proliferation and promoted differentiation. Mechanistic investigations revealed that the tumor-promoting effects of Nestin were mediated by binding to Gli3, a zinc finger transcription factor that negatively regulates hedgehog signaling. Nestin binding to Gli3 blocked Gli3 phosphorylation and its subsequent proteolytic processing, thereby abrogating its ability to negatively regulate the hedgehog pathway. Our findings show how Nestin drives hedgehog pathway-driven cancers and uncover in Gli3 a therapeutic target to treat these malignancies.
Project description:Mutations in the SFTPC gene associated with interstitial lung disease in human patients result in misfolding, endoplasmic reticulum (ER) retention, and degradation of the encoded surfactant protein C (SP-C) proprotein. To identify candidate genes involved in ER quality control of SP-C, HEK293 cells were transiently transfected with mutant SP-C (SP-CΔexon4 or SP-CL188Q), SP-CWT, or vector cDNAs, and global changes in gene expression were assessed by microarray analyses. Microarray analysis demonstrated that the SPC exon 4 deletion and SPC L188Q mutations invoke very similar transcriptional profiles including the activation of major players mediating ER response and unfolding protein response (UPR) in transient transfection system. In combination with promoter scan (UPRE, ERSE, XBP1 sites) and protein domain analysis (Finding ER Lumen, ER Membrane retention signal, J-Domain and Leucine Zipper domain), we were able to not only verify the known ERAD components (XBP1, Bip, Erdj4&5), but also identify multiple ER components which may play critical roles in the detection and /or degradation of mutant SPC, which in turn will help us to gain better understanding of the entire mammalian ERAD machinery.