A humanized mouse strain that develops spontaneously immune-mediated diabetes.
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA636755 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:The clinical management of type 1 diabetes (T1D) faces the lack of fully predictive biomarkers and of antigen-specific therapies to prevent its development. From a therapeutic standpoint, preclinical modls of T1D have fallen short of directly translating into the human. To circumvent this limitation, we developed a new mouse model that is deficient for expression of murine major histocompatibility complex class I, class II and of murine insulin genes and instead expresses HLA-A*02:01, the high susceptibility HLA-DQ8 molecule and human insulin. The metabolic and immune phenotype of these mice is basically identical to that of the parental strains. Upon expression of B7.1 under the control of the rat insulin promoter, these mice develop T1D along with a T-lymphocyte response to human preproinsulin epitopes spanning the whole autoantigen sequence. This new model will allow evaluating peptide-based immunotherapy that may directly apply to human T1D.
2021-06-02 | GSE151644 | GEO
Project description: Not available
| S-EPMC8551915 | biostudies-literature
Project description:Background: Chronic exposure to inorganic arsenic (iAs) has been associated with type 2 diabetes (T2D). However, potential sex divergence and the underlying mechanisms remain understudied. iAs is not metabolized uniformly across species, which is a limitation of typical exposure studies in rodent models. The development of a new “humanized” mouse model overcomes this limitation. In this study, we leverage this model to study sex differences in the context of iAs exposure. Objectives: The aim of this study iwas to determine if males and females exhibit different liver and adipose molecular profiles and metabolic phenotypes in the context of iAs exposure. Methods: Our study was performed on wild-type (WT) 129S6/SvEvTac and humanized arsenic +3 methyl transferase (human AS3MT) 129S6/SvEvTac mice treated with 400 ppb of iAs via drinking water ad libitum. After 1 month, mice were sacrificed and the liver and epididymales gonadal adipose depot were harvested for iAs quantification as well as sequencing-based microRNA and gene expression analysis. Serum blood was collected for fasting blood glucose, fasting plasma insulin, and HOMA-IR. Results: We detected sex divergence in liver and adipose markers of diabetes (e.g., insulin signaling pathways, fasting blood glucose, fasting plasma insulin, and HOMA-IR) only in humanized (not WT) male mice. In humanized female mice, numerous genes that promote insulin sensitivity and glucose tolerance in both the liver and adipose are elevated compared to humanized male mice. We also identified Klf11 as a putative master regulator of the sex divergence in gene expression in humanized mice. Discussion: Our study underscoreds the importance of future studies leveraging the humanized mouse model to study iAs-associated metabolic disease. The findings also suggest suggested that humanized females are protected from metabolic dysfunction relative to humanized males in the context of iAs exposure. Future investigations should focus on the detailed mechanisms that underlie the sex divergence, including the potential role of miR-34a and/or Klf11.
2023-07-03 | GSE236059 | GEO
Project description:Glioblastoma (GBM) is the deadliest primary brain tumor in adults, and progress in therapy development has been hindered by the lack of preclinical models that faithfully recapitulate interactions between human tumor cells and human immune cells, particularly in therapy-resistant disease. To address this limitation, we established a humanized mouse model of GBM using radiation-resistant patient-derived xenografts (PDXs) implanted into immunodeficient mice reconstituted with human hematopoietic stem progenitor cells derived from umbilical cord blood. For single-cell RNA sequencing, peripheral blood (PB), tumor-infiltrating immune cells (TILs), and tumor cells were collected from humanized NOG-EXL mice bearing EGFP-positive JX14P-RT tumors. Tumor cells from the same JX14P-RT model implanted into non-humanized naive NOG-EXL mice were also analyzed for comparison. Single-cell suspensions were prepared from tumor tissues, and CD45-positive immune cells and EGFP-positive tumor cells were isolated by cell sorting. Human CD45-positive cells in peripheral blood were purified separately. The dataset includes three TIL samples from humanized mice, three PB samples from humanized mice, three tumor-cell samples from humanized mice, and two tumor-cell samples from naive mice. Individual samples were labeled with hashtag oligonucleotide antibodies, pooled, and then analyzed separately by compartment as TIL, PB, and tumor groups. Libraries were generated using the 10x Genomics Chromium Single Cell 3' platform and sequenced on an Illumina NovaSeq 6000. The data show infiltration of diverse human immune populations, including T cells, natural killer cells, and myeloid lineage cells, and support the utility of this model for studying the immune microenvironment of recurrent and therapy-resistant GBM.
2026-04-19 | GSE327941 | GEO
Project description:We analysed the combined effects of exposure to maternal diabetes and disrupted HIF-1 signaling on the transcriptom in cardiac left ventricles of 12 weeks old male mice. This approach provides the information about the long term changes originating in utero due to maternal diabetes and inefficient response to hypoxia which develops as a result of hyperglycemia. The majority of changes were detected in Hif1a insufficient mice exposed to maternal diabetes.
2018-05-15 | GSE109633 | GEO
Project description:Discoidin domain-containing receptor 1 (DDR1) plays an important role in cancer progression. However, the DDR1 function in tumors is still elusive. We recently reported that DDR1 promoted collagen fiber alignment and formation of a physical barrier, which causes immune exclusion from tumors. We also demonstrated that our DDR1 ECD-targeting mAbs can disrupt collagen fiber alignment and increase T Cell infiltration in tumors. In this study, we humanized a DDR1 ECD-targeting mAb and showed significant antitumor efficacy in an immunocompetent mouse model. We determined the binding epitope using gene mutagenesis, hydrogen-deuterium exchange mass spectrometry (HDX-MS), and X-ray crystallography. Mechanistically, we showed that the humanized mAb inhibited DDR1 phosphorylation and, more importantly, blocked DDR1 shedding and disrupted a physical barrier formed by collagen fiber alignment in tumors. This study not only paves a pathway for development of PRTH-101 as a cancer therapeutic, but also broaden our understanding of the roles of DDR1 in modulation of collagen alignments in tumor extracellular matrix and tumor immune microenvironment.
2023-06-19 | PXD042971 | Pride
Project description:Previously, we developed a new model of diabetes-induced wound healing impairment in skin-humanized mice models that faithfully recapitulates the major histo-physiological features of such skin repair-deficient condition. Aiming to dissect the molecular mechanisms responsible for the delayed wound closure, global gene expression studies were performed.
2021-02-01 | GSE147890 | GEO
Project description:In order to understand the mechanisms underlying diabetes mellitus, we conducted a transcriptomic profiling of the liver from Macaca fascicularis with spontaneously occurred diabetes mellitus at their middle age compared with the monkeys fed with the same food and high-fat and high-sugar diet, respectively.
2022-05-05 | E-MTAB-10493 | biostudies-arrayexpress
Project description: Not available
| S-EPMC4956255 | biostudies-literature