Project description:FGF21 analogs tested in clinical trials in metabolic diseases i.e. type 2 diabetes mellitus and non-alcoholic fatty liver disease are generally well-tolerated. FGF21 is a peptide hormone that is primarily secreted by the liver, but it also crosses the blood-brain barrier. The bulk of literature on this subject has raised the possibility that FGF21 administration could affect alcohol use and reward behaviors. Our recent study showed that FGF21 levels were associated with recent alcohol consumption. Furthermore, our data also suggest that the effects of FGF21 in the induced pluripotent stem cell (iPSC)-derived 3D-brain organoids are associated, at least in part, with the regulation of catecholamines, neurotransmitters that play a crucial role in reward pathways. These observations potentially open the way to pharmacologic manipulation of FGF21, which in turn could have significant implications for catecholamines, and alcohol use. Current in vitro models designed to study drug action in the human brain are limited. Therefore, we used iPSC-derived neurons as a novel "cell-line based" approach to advance our understanding of drug action in the brain. Since the half-life of the naïve form of FGF21 is about 0.5-2 hours, it is not suitable for clinical use due to poor pharmacokinetic and biophysical properties . As a result, the present study was designed to identify molecular mechanisms for both the naïve form of FGF21 and a long-acting FGF21 molecule (PF-05231023) which was developed by conjugating two molecules of modified FGF21 (dHis/Ala129Cys) to an antibody scaffold.
Project description:Proteostasis involves a dynamic network of biological pathways that regulate protein synthesis, maintenance, and degradation. As postmitotic cells, neurons are particularly sensitive to environmental changes, and dysfunction in cellular proteostasis can lead to an accumulation of aggregated and misfolded proteins. However, how proteins turnover on a global scale in human neurons is not well understood. In this study, we systematically improved a dynamic SILAC proteomic approach to enable a deep and accurate measurement of protein turnover in human induced pluripotent stem cell (iPSC)-derived cholinergic spinal motor and glutamatergic cortical neurons. Furthermore, we applied this deep proteome turnover method to evaluate how inhibiting the ubiquitin-proteasome and lysosome-autophagy pathway impacts proteostasis in iPSC-derived neurons. Using these datasets, we developed a freely available resource called Neuron Profile, an interactive website for visualizing and querying protein turnover in subcellular locations in human neurons.
Project description:Analysis of TERT-dependent global gene expression changes in iPSC-derived human AD neurons. The hypothesis tested in the present study was that TERT influences the regulation of gene expressions in the iPSC-derived human neurons. Results provide important information of the response of iPSC-derived neurons in presence and absence of TERT induction.
Project description:In this dataset, we studied human dopaminergic neuron differenation from induced pluripotent stem cells (iPSCs). We included the gene expression data obtained from iPSCs and iPSC-derived dopaminergic neurons. This dataset is used to predict chromatin accessibility in iPSCs and iPSC-derived neurons using BIRD (Big data Regression for predicting DNase I hypersensitivity).
Project description:TDP-43 is a key splicing regulator. Here, we perform ribosome profiling on iPSC-derived neurons to examine how translation is affected by TDP-43 knockdown.