Microarray analysis to investigate the global expression of miRNAs in pediatric T1D patients in comparison to non-diabetic controls.
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ABSTRACT:
PROVIDER: PRJNA430258 | ENA |
REPOSITORIES: ENA
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Project description:MicroRNAs (miRNAs) are small non-coding RNAs that target multiple mRNAs and regulate gene expression. The implication of miRNAs in T1D pathogenesis, as potential modulators of immune response genes, remains poorly defined. The aim of this study was to investigate the expression profile of miRNAs in new onset T1D to identify autoimmune associated miRNAs.
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Project description:Non-obese diabetic (NOD) mice feature pancreatic infiltration of autoreactive T lymphocytes as early as 1 month of age, which destruct insulin-producing beta-cells to finally emerge autoimmune diabetes mellitus (T1D) within 8 months. In view, we hypothesized that during the development of T1D, transcriptional modulation of immune reactivity genes may occur as thymocytes mature toward peripheral T lymphocytes. Transcriptome of thymocytes and peripheral CD3+ T lymphocytes from pre-diabetic or diabetic mice analyzed through microarray hybridizations allowed observation of 3,586 differentially expressed genes. Hierarchical clustering grouped mice according to age/T1D onset and genes to their ontology. Transcriptional activity of thymocytes toward peripheral T lymphocytes unraveled sequential participation of genes involved with CD4+/CD8+ T cell differentiation (Themis), tolerance induction (Foxp3), apoptosis (Fasl) to soon after T cell activation (IL4), while the emergence of T1D coincided with the expression of cytotoxicity (Crtam) and inflammatory response genes (Tlr) by peripheral T lymphocytes.
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Project description:Type 1 Diabetes (T1D) is characterized by autoimmune-mediated destruction of insulin-producing beta-cells. Recent research has focused on the role of the innate immune system in initiating this process. To investigate this further, we used m6A-profiling of human islets from non-diabetic individuals and the human beta-cell line EndoC-bH1 treated with PBS or interleukin 1 beta and interferon alpha, as well as established T1D patients. Our findings reveal that N6-Methyladenosine (m6A) is a mechanism that helps protect beta-cells by accelerating the decay of mRNA from the 2'-5'-oligoadenylate synthetase (OAS) genes, which controls the antiviral innate immune response at the onset of T1D. These results provide insight into the adaptive safeguarding mechanisms of beta-cells and the role of m6A in T1D development, highlighting potential targets for therapeutic interventions.
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Project description:Our current understanding of the pathogenesis of T1D arose in large part from studies using the non-obese diabetic (NOD) mouse model of type 1 diabetes (T1D). Of concern, therapeutic interventions shown to significantly dampen or even reverse disease in mouse models have not successfully translated into interventions in human T1D. The present study addresses this disconnect in research translation by directly analyzing human donor islets from individuals with T1D, aiming to provide insight into disease mechanisms and identify potential target pathways for therapeutic intervention. We obtained human islets from a young individual with short-duration T1D, an older individual with long-duration T1D and three non-diabetic donors, and performed unbiased functional genomic analysis by high depth RNA sequencing on these unique cases. This analysis identified several inflammatory pathways upregulated in short-duration disease, which surprisingly included many components of innate immunity. Subsequent manipulation of one of these pathways/factors in NOD mice resulted in a significant reduction in diabetes progression when inhibition occurred early in disease progression. Taken together our data demonstrates that the direct analysis of human islets is essential for identifying relevant and promising novel targets for translation into effective therapeutic interventions for human T1D.
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Project description:We recently reported the scalable in vitro production of functional stem cell-derived β cells. Here we extend this approach to generate SC-β cells from Type 1 diabetic patients (T1D), a cell type that is destroyed during disease progression and has not been possible to extensively study. These cells express β cell markers, respond to glucose both in vitro and in vivo, prevent alloxan-induced diabetes in mice, and respond to anti-diabetic drugs. Furthermore, we use an in vitro disease model to demonstrate the cells respond to different forms of β cell stress. Using these assays, we find no major differences in T1D SC-β cells compared to SC-β cells derived from non-diabetic patients (ND). These results show that T1D SC-β cells can be used for the treatment of diabetes, drug screening, and the study of β cell biology.
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