Redirecting microglia phenotype via inhibition of NFAT1 ameliorates deficits in mouse model of synucleinopathies
Ontology highlight
ABSTRACT: We evaluated the potential of NFAT1 inhibition as a new therapeutic strategy for synucleinopathies utilizing in vitro and in vivo synucleinopathy models.
Project description:Expression data from antigen-experienced Nfat1+/+ and Nfat1-/- CD4+ T cells following 21 days of Plasmodium yoelii 17XNL infection.
Project description:To characterize the roles of NFAT1 in the pathogenesis of autoimmune myasthenia gravis (MG) at a genome-wide scale, we performed gene expression microarray analysis for wild-type (WT) and NFAT1 KO bone marrow-derived dendritic cells (BMDCs) with or without 2h and 12h-stimulation with pam3CSK4.
Project description:NFAT1 is a transcription factor that elicits breast carcinoma cells to become invasive, contributing thus to formation of metastases. The molecular mechanisms by which NFAT1 operates in this respect are still poorly known. Here, we report that NFAT1 increases Lipocalin 2 (LCN2) mRNA and protein expression by binding to specific sites in the LCN2 gene promoter region. We show that the LCN2 protein is required downstream of NFAT1 to increase breast cancer cell invasion. We demonstrate that the NFAT1/LCN2 axis is sufficient to regulate expression of the TNF-like receptor TWEAKR at the RNA level and of its ligand, TWEAK, at the protein level. We show, however, that TWEAKR mediates an anti-invasive effect in breast cancer cells whereas, depending on LCN2 expression, TWEAK has either anti- and pro-invasive capacities. Thus, we identify LCN2 and TWEAKR/TWEAK as critical downstream effectors of NFAT1 to regulate breast cancer cell motility and invasive capacity.
Project description:To investigate the impact of the Nfat1 knockout on pain processing-associated genes in the spinal cord, we performed microarray analysis.
Project description:We generated genome-wide chromatin-state maps of mouse dendritic cells in steady and dectin-1 activated with or without NFAT inhibitor FK506. We found the differential H3K4me3 signatures in these cells. This study provides the epigenetic signatures of steady, dectin-1activated with or without NFAT inhibition. We also generated stable dendritic cell line D1 expressing a V5 tagging NFAT1. This cell line was used to map the global binding sites of NFAT1 upon dectin-1 activation with 10ug/ml curdlan for 30 minutes. examine NFAT1-v5 genome wide binding sites and differential H3K4me3 epigenetic modification in steady, dectinn-1 activated with or without NFAT inhibiton.
Project description:4T1 is a mammary tumor cell line to which the NFAT1 transcription factor is essential for tumorigenesis and metastasis. control or shRNA transduced 4T1 cells growing in culture were collected and RNA was extracted from each sample and processed for hybridization to Affymetrix arrays.
Project description:Multiple systems atrophy (MSA) is a unique synucleinopathy of unknown cause characterized by alpha-synuclein aggregates in oligodendroglia. Here, we used the in-situ proximity labeling technique biotinylation (BAR) by antibody recognition to identify alpha-synuclein interactomes in the MSA brain and compare them with other common synucleinopathies.
Project description:We isolated peripheral blood mononuclear cells from whole blood from an NFAT1 deficient patient and 5 healthy controls. Cells were either treated with PMA (50ng/mL) + 1uM Ionomycin for 4 hours, or left untreated. Cells were then isolated in nanowells, and incubated with single mRNA-capture beads. mRNA from these beads were used for library preparation and sequenced. Raw counts were used for clustering analysis and differential expression. This analysis pointed to defects in NFAT1 deficient patient's B-cells and T-cells that could be contributing the observed B-cell malignancy