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12-Lipoxygenase Inhibition Suppresses Islet Immune and Inflammatory Responses and Delays Autoimmune Diabetes in Human Gene Replacement Mice.

ABSTRACT: 12-Lipoxygenase Inhibition Suppresses Islet Immune and Inflammatory Responses and Delays Autoimmune Diabetes in Human Gene Replacement Mice.

PROVIDER: PRJNA1137967 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR29896700_1.fastq.gz	Fastqsanger.gz
	SRR29896700_2.fastq.gz	Fastqsanger.gz
	SRR29896701_1.fastq.gz	Fastqsanger.gz
	SRR29896701_2.fastq.gz	Fastqsanger.gz
	SRR29896702_1.fastq.gz	Fastqsanger.gz

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12-Lipoxygenase Inhibition Suppresses Islet Immune and Inflammatory Responses and Delays Autoimmune Diabetes in Human Gene Replacement Mice

Project description:12-Lipoxygenase Inhibition Suppresses Islet Immune and Inflammatory Responses and Delays Autoimmune Diabetes in Human Gene Replacement Mice

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12-Lipoxygenase Inhibition Suppresses Islet Immune and Inflammatory Responses and Delays Autoimmune Diabetes in Human Gene Replacement Mice

Project description:Type 1 diabetes (T1D) is characterized by the autoimmune destruction of insulin-producing β cells and involves an interplay between β cells and cells of the innate and adaptive immune systems. We investigated the therapeutic potential of targeting 12-lipoxygenase (12-LOX), an enzyme implicated in inflammatory pathways in β cells and macrophages, using a mouse model in which the endogenous mouse Alox15 gene is replaced by the human ALOX12gene. Our findings demonstrate that VLX-1005, a potent 12-LOX inhibitor, effectively delays the onset of autoimmune diabetes in human gene replacement non-obese diabetic (NOD) mice. By spatial proteomics analysis, VLX-1005 treatment resulted in marked reductions in infiltrating T and B cells and macrophages with accompanying increases in immune checkpoint molecules PD-L1 and PD-1, suggesting a shift towards an immune-suppressive microenvironment. RNA sequencing analysis of isolated islets from inhibitor-treated mice revealed significant alteration of cytokine-responsive pathways. RNA sequencing of polarized proinflammatory macrophages showed that VLX-1005 significantly reduced the interferon response. This study highlights a functional equivalence of human ALOX12 and mouse Alox15 in T1D pathogenesis. Our studies provide a platform for the preclinical evaluation of LOX inhibitors and supports the development of 12-LOX inhibitors as a therapeutic strategy for T1D and other inflammatory diseases.

2024-08-23 | GSE272668 | GEO

12-Lipoxygenase Inhibition Suppresses Islet Immune and Inflammatory Responses and Delays Autoimmune Diabetes in Human Gene Replacement Mice.

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12-Lipoxygenase inhibition suppresses islet immune and inflammatory responses and delays autoimmune diabetes in human gene replacement mice.

Project description:Type 1 diabetes (T1D) is characterized by the autoimmune destruction of insulin-producing β cells and involves an interplay between β cells and cells of the innate and adaptive immune systems. We investigated the therapeutic potential of targeting 12-lipoxygenase (12-LOX), an enzyme implicated in inflammatory pathways in β cells and macrophages, using a mouse model in which the endogenous mouse Alox15 gene is replaced by the human ALOX12 gene. Our findings demonstrate that VLX-1005, a potent 12-LOX inhibitor, effectively delays the onset of autoimmune diabetes in human gene replacement non-obese diabetic (NOD) mice. By spatial proteomics analysis, VLX-1005 treatment resulted in marked reductions in infiltrating T and B cells and macrophages with accompanying increases in immune checkpoint molecules PD-L1 and PD-1, suggesting a shift towards an immune-suppressive microenvironment. RNA sequencing analysis of isolated islets from inhibitor-treated mice revealed significant alteration of cytokine-responsive pathways. RNA sequencing of polarized proinflammatory macrophages showed that VLX-1005 significantly reduced the interferon response. Our studies demonstrate that the ALOX12 human replacement gene mouse provides a platform for the preclinical evaluation of LOX inhibitors and supports VLX-1005 as an inhibitor of human 12-LOX that engages the enzymatic target and alters the inflammatory phenotypes of islets and macrophages to promote the delay of autoimmune diabetes.

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Whole population RNASeq of pancreatic islet macrophages during autoimmune diabetes progression

Project description:Whole population RNASeq of pancreatic islet macrophages during autoimmune diabetes progression.

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Treg insufficiency in autoimmune diabetes is driven by selective loss of Neuropilin-1 on intra-islet regulatory T cells

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Whole population RNASeq of pancreatic islet macrophages during autoimmune diabetes progression

Project description:Whole population RNASeq of pancreatic islet macrophages during autoimmune diabetes progression

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An early islet transcriptional signature drives local inflammation in autoimmune diabetes

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microRNA and mRNA expression profiles of human pancreatic islet-like cell clusters

Project description:Type 1 diabetes is an autoimmune destruction of pancreatic islet beta cell disease, and it is important to find new alternative source of the islet beta cells to replace the damaged cells. Human embryonic stem (hES) cells possess unlimited self-renewal and pluripotency and thus have the potential to provide an unlimited supply of different cell types for tissue replacement. The hES-T3 cells with normal female karyotype were first differentiated into embryoid bodies and then induced to generate the pancreatic islet-like cell clusters, which expressed pancreatic islet cell-specific markers of insulin, glucagon and somatostatin. The expression profiles of microRNAs and mRNAs from the pancreatic islet-like cell clusters were further analyzed and compared with those of undifferentiated hES-T3 cells and differentiated embryoid bodies. MicroRNAs negatively regulate the expression of protein-coding mRNAs. The pancreatic islet-like cell clusters were found to exhibit very high expression of microRNAs miR-186, miR-199a and miR-339, which down-regulated the expression of LIN28, PRDM1, CALB1, GCNT2, RBM47, PLEKHH1, RBPMS2 and PAK6. Therefore, these microRNAs are very likely to play important regulatory roles in the differentiation of pancreatic islet cells and early embryonic development. In this investigation, both miRNA and mRNA expression profiles from the pancreatic islet-like cell clusters differentiated from hES-T3 cells (T3pi) were quantitatively determined and compared with those of undifferentiated hES-T3 cells grown on mouse embryonic fibroblast (MEF) feeder (T3ES) and embryoid bodies differentiated from hES-T3 cells (T3EB). Several target genes of pancreatic islet cell-specific miRNAs were identified. ***This submission represents the mRNA expression component of the study only***

2010-09-29 | E-GEOD-14503 | biostudies-arrayexpress

microRNA and mRNA expression profiles of human pancreatic islet-like cell clusters

2010-09-30 | GSE14503 | GEO