Single-cell RNA-seq uncovers the early alterations of retina in type 2 diabetes mice
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE205123 | GEO | 2022/06/03
REPOSITORIES: GEO
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Project description:Diabetic retinopathy is one of the leading causes of blindness in diabetic patients. Emerging evidence suggests that retinal neurodegeneration is an early event in the pathogenesis of diabetic retinopathy, but the underlying causes of neuronal loss are unknown. To unravel potential mechanisms underlying early retinal neurodegeneration in diabetic retinopathy, a gene expression profiling study was undertaken to compare the gene expression in retinas of 8-week db/db diabetic mice with that of lean non-diabetic littermates. Retinas were obtained from 8-week db/db diabetic mice and age-matched lean non-diabetic controls. Total RNA was extracted and processed for being hybridized onto affymetrix DNA microarrays.
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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.
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Project description:Diabetic retinopathy is one of the leading causes of blindness in diabetic patients. Emerging evidence suggests that retinal neurodegeneration is an early event in the pathogenesis of diabetic retinopathy, but the underlying causes of neuronal loss are unknown. To unravel potential mechanisms underlying early retinal neurodegeneration in diabetic retinopathy, a gene expression profiling study was undertaken to compare the gene expression in retinas of 8-week db/db diabetic mice with that of lean non-diabetic littermates.
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Project description:Diabetic retinopathy (DR) is one of the main causes of blindness in working age populations in industrialized countries. It is estimated that close to 100 million individuals worldwide suffer from DR. Regrettably, relatively little is known of the cellular processes at play during late stages of the disease, especially concerning diabetic macular edema (DME). Streptozotocin-induced diabetic retinopathy (STZ) allows to reproduce experimentally in the mouse retina the retina vascular leakage and neuroegeneration features observed in human pathological retina with non-proliferative DR. Using agnostic and orthogonal approaches, in our work we demonstrate that in contrast to healthy retina, the STZ diabetic retina engages pathways of cell cycle arrest, resulting in cellular senescence. These findings combined with further pharmacological approaches provide mechanistic evidence supporting that targeting selectively senescent vessels in DR represents a potential treatment for high vascular permeability in DME.
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Project description:Diabetic retinopathy (DR) is a common microvascular complication that may cause severe visual impairment and blindness in patients with type 2 diabetes mellitus (T2DM). Early detection of DR will provide opportunities for more treatment options and better control of disease progression. Effective biomarkers, which are not currently available, may improve clinical outcomes through precise diagnosis and prognosis. We sought to develop a non-invasive diagnostic approach for diabetic retinopathy among type 2 diabetes mellitus based on 5-hydroxymethylcytosines (5hmC), an emerging epigenetic marker, in circulating cell-free DNA (cfDNA)
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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
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Project description:Schemic retinopathies such as diabetic retinopathy (DR) and retinopathy of prematurity (ROP), are the main causes of blindness in working age and pediatric populations in industrialized countries. It is estimated that close to 100 million individuals worldwide suffer from DR and 15 million preterm infants born each year are predisposed to ROP. Regrettably, relatively little is known of the cellular processes at play during late stages of pathological angiogenesis in these diseases and consequently current standards of care target all neovascularization. Oxygen-induced retinopathy (OIR) allows to reproduce experimentally in the mouse retina the pathological features observed in human pathological retina such as ischemic avascular regions as well as epi-retinal neovascularization. Using agnostic and orthogonal approaches, in our work we demonstrate that in contrast to healthy blood vessels, pathological vessels engage pathways of cell cycle arrest, resulting in cellular senescence. These findings combined with further genetic and pharmacological approaches provide mechanistic evidence supporting that targeting selectively senescent vessels in DR represents a potential treatment for neovascular retinal disease.
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Project description:Diabetic retinopathy (DR) is an irreversible and progressive diabetic complication leading to visual impairment, even blindness. Due to the delicate and complicated structure of the retina, the pathology of DR has not been completely elucidated yet. We constructed a transcriptome atlas of >14,000 single cells from healthy and streptozotocin (STZ)-induced diabetic murine retinas to decipher pathological alterations of DR. We found four stress-inducible genes Cirbp, Rmb3, Mt1 and Mt2 commonly induced in most types of retinal cells. Bipolar cells were little affected both in number and gene expression. There existed two subtypes of Müller cells, the Fos-expressing subtype and the no-marker subtype, and the latter lost more in DR. A large number of genes were deregulated in diabetic vascular endothelial cells (ECs), and the differential expression genes were paired to the pathways functioning in metabolism, shear stress and vascular permeability. These pathways were mapped by more differential expression genes in a subpopulation of ECs specifically presented in diabetic retinas (diabetic retinal ECs, DRECs). Moreover, several inflammation pathways were activated in DRECs, and the most significant one is the IL-17 signaling pathway. According to the EC markers, DRECs were mainly capillary ECs, confirmed by immunofluorescent staining of S100a9, a target gene of the IL-17 signaling pathway. This study deciphered pathological alterations of DR, and provided clues for new potential targets for DR therapy.
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