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PDZK1 Protects Against RPE Senescence by Targeting the 14-3-3ε-mTOR Axis to Attenuate Early Diabetic Retinopathy [MG_HG]

ABSTRACT: In diabetic retinopathy (DR), hyperglycemia induces retinal pigment epithelium (RPE) cell senescence via downregulation of PDZK1. PDZK1 overexpression counteracts senescence by binding 14-3-3ε to modulate mTOR signaling, reducing oxidative stress and enhancing autophagy. Both genetic PDZK1 restoration and pharmacologic senolysis (Nutlin-3a) attenuate retinal senescence and ameliorate early DR pathology, establishing the PDZK1-14-3-3ε-mTOR axis as a therapeutic target

ORGANISM(S): Homo sapiens

PROVIDER: GSE304690 | GEO | 2025/08/11

REPOSITORIES: GEO

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PDZK1 Protects Against RPE Senescence by Targeting the 14-3-3ε-mTOR Axis to Attenuate Early Diabetic Retinopathy

Project description:In diabetic retinopathy (DR), hyperglycemia induces retinal pigment epithelium (RPE) cell senescence via downregulation of PDZK1. PDZK1 overexpression counteracts senescence by binding 14-3-3ε to modulate mTOR signaling, reducing oxidative stress and enhancing autophagy. Both genetic PDZK1 restoration and pharmacologic senolysis (Nutlin-3a) attenuate retinal senescence and ameliorate early DR pathology, establishing the PDZK1-14-3-3ε-mTOR axis as a therapeutic target

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Extracellular vesicles of human diabetic retinopathy retinal tissue and urine of diabetic retinopathy patients analyzed using mass spectrometry

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In-depth transcriptomic analyses investigating molecular mechanisms underlying diabetic retinopathy (smallRNA)

Project description:Diabetic Retinopathy (DR) is among the major global causes for vision loss. With the rise in diabetes prevalence, an increase in DR incidence is expected. Current understanding of both the molecular etiology and pathways involved in the initiation and progression of DR is limited. Here we analyzed mRNA and miRNA expression profiles of 80 human post-mortem retinal samples from 80 patients diagnosed with various stages of DR. We found differentially expressed transcripts to be predominantly associated with late stage DR and pathways such as hippo and gap junction signaling. A multivariate regression model identified transcripts with progressive changes throughout disease stages, which in turn displayed significant overlap with sphingolipid and cGMP−PKG signaling. Combined analysis of miRNA and mRNA expression further uncovered disease-relevant miRNA/mRNA associations as potential mechanisms of post-transcriptional regulation. Finally, integrating human retinal single cell RNA-Sequencing data revealed a continuous loss of retinal ganglion cells, and Müller cell mediated changes in histidine and β-alanine signaling. Our findings offer an unprecedented insight into the development of DR and provide potential avenues for future therapeutic intervention.

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PDZK1 Protects Against RPE Senescence by Targeting the 14-3-3ε-mTOR Axis to Attenuate Early Diabetic Retinopathy

Project description:PDZK1 Protects Against RPE Senescence by Targeting the 14-3-3ε-mTOR Axis to Attenuate Early Diabetic Retinopathy

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Project description:In diabetic retinopathy (DR), a blinding disease, retinal microglia-induced inflammatory responses precede microangiopathy. However, the binary concept of microglial M1/M2 polarization paradigms during inflammatory activation has been debated. In this study, we confirmed microglia had the most significant changes in early DR using single-cell RNA sequencing. Besides, at cellular level three new microglial subtypes were defined, including two M1 types (Egr2+ M1 and Egr2- M1) and one M2 type. We also revealed the anatomical locations, different activation orders, mutual activation regulation mechanisms and dynamic changes in polarization phenotypes between these subtypes. Furthermore, we constructed an inflammatory network involving microglia, blood-derived macrophages and other retinal nonneuronal cells. The targeted study of new disease-specific microglial subtypes can shorten the time for drug screening and clinical application, which provided insight for the early control and reversal of DR.

2022-11-25 | GSE209872 | GEO

PDZK1 Protects Against RPE Senescence by Targeting the 14-3-3ε-mTOR Axis to Attenuate Early Diabetic Retinopathy [MG_HG]

Project description:PDZK1 Protects Against RPE Senescence by Targeting the 14-3-3ε-mTOR Axis to Attenuate Early Diabetic Retinopathy [MG_HG]

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