Transcriptomic comparison of the retina in two mouse models of diabetes.
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ABSTRACT:
SUBMITTER: Freeman WM
PROVIDER: S-EPMC2816812 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Mouse models of type I diabetes offer the potential to combine genetic approaches with other pharmacological or physiological manipulations to investigate the pathophysiology and treatment of diabetic retinopathy. Type I diabetes is induced in mice through chemical toxins or may arise spontaneously from genetic mutations. Both models are associated with retinal vascular and neuronal changes. Retinal transcriptomic responses in C57BL/6J mice treated with strepotozotocin and Ins2Akita were compared after 3 months of hyperglycemia. Specific gene expression changes suggest a neurovascular inflammatory response in diabetic retinopathy. Genes common to the two models may represent the response of the retina to hyperglycemia; while changes unique to each model may represent time-dependent disease progression differences in the various models. Further investigation of the commonalities and differences between mouse models of type I diabetes may define cause and effect events in early diabetic retinopathy disease progression.
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Project description:Peripheral neuropathy (PN) is a complication of prediabetes and type 2 diabetes (T2D). Increasing evidence suggests that factors besides hyperglycaemia contribute to PN development, including dyslipidaemia. The objective of this study was to determine differential lipid classes and altered gene expression profiles in prediabetes and T2D mouse models in order to identify the dysregulated pathways in PN. Here, we used high-fat diet (HFD)-induced prediabetes and HFD/streptozotocin (STZ)-induced T2D mouse models that develop PN. These models were compared to HFD and HFD-STZ mice that were subjected to dietary reversal. Both untargeted and targeted lipidomic profiling, and gene expression profiling were performed on sciatic nerves. Lipidomic and transcriptomic profiles were then integrated using complex correlation analyses, and biological meaning was inferred from known lipid-gene interactions in the literature. We found an increase in triglycerides (TGs) containing saturated fatty acids. In parallel, transcriptomic analysis confirmed the dysregulation of lipid pathways. Integration of lipidomic and transcriptomic analyses identified an increase in diacylglycerol acyltransferase 2 (DGAT2), the enzyme required for the last and committed step in TG synthesis. Increased DGAT2 expression was present not only in the murine models but also in sural nerve biopsies from hyperlipidaemic diabetic patients with PN. Collectively, these findings support the hypothesis that abnormal nerve-lipid signalling is an important factor in peripheral nerve dysfunction in both prediabetes and T2D.This article has an associated First Person interview with the joint first authors of the paper.
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Project description:Diabetes is a disease now affecting more than 20 million people in the United States alone. When left untreated it has numerous debilitating effects including diabetic retinopathy, which is characterized by the death of retinal neurons as well as a breakdown of the retinal vascularization. This leads to nearly 24,000 cases of blindness each year among diabetic patients. Studies have shown the importance of both nitric oxide and the gene VEGF in retinopathy, however little is known about the condition's progression. This study would determine which genes are affected early in diabetes and more generally, give insite into how neural degeneration occurs in the retina. We aim to show the gene-level changes in the diabetic mouse retina five weeks after induction of diabetes. Our laboratory's primary focus is on NO production through nNOS, iNOS and endothelial (eNOS). We hope to be able to correlate some of the transcript level changes with genes known to be involved in the NO signalling pathways. Previous data by our lab and others have shown that neuronal nitric oxide synthase (nNOS) and inducible NOS (iNOS) are upregulated under diabetic conditions in the retina. Additional work in our lab has shown that the lack of nitric oxide (NO) produced by nNOS may affect neurotransmitter production, particularly with GABA. We have also shown that mice with induced diabetes show neurochemical changes in the retina after only one to three weeks. Thus, we expect to see gene level changes associated with the retina before psysological changes in newly diabetic mice. Adult CD1 mice of random sexes are injected with the drug streptozotocin on three successive days while fasting 8 hours before the injection. This drug selectivley destroys the beta-islet cells of the pancrease. Their blood sugar levels are then tested after a resting period. Mice with glucose levels above 250mg/dL are considered diabetic from the date of the last injection. Mice are then sacrificed after the waiting period by breif isoflourine inhalation followed by decapitation. Retinas are immediately removed in cold HBSS and RNA is extracted using Trizol extraction. To get adequate amounts of RNA, we will pool four retinas (2 animals) together. Keywords: dose response
2008-08-30 | GSE12610 | GEO
Project description:The retina, as the only visually accessible tissue in the central nervous system, has attracted significant attention for evaluating it as a biomarker for neurodegenerative diseases. Yet, most of studies focus on characterizing the loss of retinal ganglion cells (RGCs) and degeneration of their axons. There is no integrated analysis addressing temporal alterations of different retinal cells in the neurovascular unit (NVU) in particular retinal vessels. Here we assessed NVU changes in two mouse models of tauopathy, P301S and P301L transgenic mice overexpressing the human tau mutated gene, and evaluated the therapeutic effects of a tau oligomer monoclonal antibody (TOMA). We found that retinal edema and breakdown of blood-retina barrier were observed at the very early stage of tauopathy. Leukocyte adhesion/infiltration, and microglial recruitment/activation were constantly increased in the retinal ganglion cell layer of tau transgenic mice at different ages, while Müller cell gliosis was only detected in relatively older tau mice. Concomitantly, the number and function of RGCs progressively decreased during aging although they were not considerably altered in the very early stage of tauopathy. Moreover, intrinsically photosensitive RGCs appeared more sensitive to tauopathy. Remarkably, TOMA treatment in young tau transgenic mice significantly attenuated vascular leakage, inflammation and RGC loss. Our data provide compelling evidence that abnormal tau accumulation can lead to pathology in the retinal NVU, and vascular alterations occur more manifest and earlier than neurodegeneration in the retina. Oligomeric tau-targeted immunotherapy has the potential to treat tau-induced retinopathies. These data suggest that retinal NVU may serve as a potential biomarker for diagnosis and staging of tauopathy as well as a platform to study the molecular mechanisms of neurodegeneration.
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Project description:Diabetes is a disease now affecting more than 20 million people in the United States alone. When left untreated it has numerous debilitating effects including diabetic retinopathy, which is characterized by the death of retinal neurons as well as a breakdown of the retinal vascularization. This leads to nearly 24,000 cases of blindness each year among diabetic patients. Studies have shown the importance of both nitric oxide and the gene VEGF in retinopathy, however little is known about the condition's progression. This study would determine which genes are affected early in diabetes and more generally, give insite into how neural degeneration occurs in the retina. We aim to show the gene-level changes in the diabetic mouse retina five weeks after induction of diabetes. Our laboratory's primary focus is on NO production through nNOS, iNOS and endothelial (eNOS). We hope to be able to correlate some of the transcript level changes with genes known to be involved in the NO signalling pathways. Previous data by our lab and others have shown that neuronal nitric oxide synthase (nNOS) and inducible NOS (iNOS) are upregulated under diabetic conditions in the retina. Additional work in our lab has shown that the lack of nitric oxide (NO) produced by nNOS may affect neurotransmitter production, particularly with GABA. We have also shown that mice with induced diabetes show neurochemical changes in the retina after only one to three weeks. Thus, we expect to see gene level changes associated with the retina before psysological changes in newly diabetic mice. Adult CD1 mice of random sexes are injected with the drug streptozotocin on three successive days while fasting 8 hours before the injection. This drug selectivley destroys the beta-islet cells of the pancrease. Their blood sugar levels are then tested after a resting period. Mice with glucose levels above 250mg/dL are considered diabetic from the date of the last injection. Mice are then sacrificed after the waiting period by breif isoflourine inhalation followed by decapitation. Retinas are immediately removed in cold HBSS and RNA is extracted using Trizol extraction. To get adequate amounts of RNA, we will pool four retinas (2 animals) together.
2008-10-25 | E-GEOD-12610 | biostudies-arrayexpress
Project description:To study the development of the human retina, we use single-cell RNA sequencing (RNA-seq) at key fetal stages and follow the development of the major cell types as well as populations of transitional cells. We also analyze stem cell (hPSC)-derived retinal organoids; although organoids have a very similar cellular composition at equivalent ages as the fetal retina, there are some differences in gene expression of particular cell types. Moreover, the inner retinal lamination is disrupted at more advanced stages of organoids compared with fetal retina. To determine whether the disorganization in the inner retina is due to the culture conditions, we analyze retinal development in fetal retina maintained under similar conditions. These retinospheres develop for at least 6 months, displaying better inner retinal lamination than retinal organoids. Our single-cell RNA sequencing (scRNA-seq) comparisons of fetal retina, retinal organoids, and retinospheres provide a resource for developing better in vitro models for retinal disease.
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