Dataset Information

Ad- and AAV8-mediated ABCA1 gene therapy in a murine model with retinal ischemia/reperfusion injuries.

ABSTRACT: The anti-inflammatory molecule annexin A1 (ANXA1) determines the ultimate fate of retinal ganglion cell (RGC) in glaucoma. Cytoplasmic and extracellular ANXA1 facilitate resolution of inflammation. However, the nuclear translocation of ANXA1 induces RGC apoptosis in a murine glaucoma model, and the maintenance of ANXA1 secreted in the extracellular environments remains unclear. In this study, we found that intravitreal injection of the recombinant adenovirus vector (Ad)-ATP-binding cassette transporter A1 (ABCA1; carrying full-length ABCA1) improved RGC survival in the ischemia reperfusion (IR) mice model. Upregulation of ABCA1 maintained ANXA1 cytoplasmic location and reduced ANXA1 nuclear translocation, which is due to the decreased binding of ANXA1 with importin ?. Moreover, we found that amino acids 903 to 1,344 of ABCA1 interacted with ANXA1 and decreased its nuclear localization. Importantly, intravitreal injection of adenovirus-associated viral (AAV) vector AAV8-ABCA1 (carrying 903 to 1,344 fragments of ABCA1) maintained ANXA1 cytoplasmic location and improved RGC survival in the IR mice model. Thus, overexpression of ABCA1 protects against RGC apoptosis by partially blocking ANXA1 nuclear translocation. This study puts forth a potential gene treatment strategy to prevent RGC apoptosis in glaucoma.

SUBMITTER: Luo J

PROVIDER: S-EPMC7890372 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

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Ad- and AAV8-mediated <i>ABCA1</i> gene therapy in a murine model with retinal ischemia/reperfusion injuries.

Luo Jing J Wang Shengli S Zhou Zhenlong Z Zhao Yin Y

Molecular therapy. Methods & clinical development 20210126

The anti-inflammatory molecule annexin A1 (ANXA1) determines the ultimate fate of retinal ganglion cell (RGC) in glaucoma. Cytoplasmic and extracellular ANXA1 facilitate resolution of inflammation. However, the nuclear translocation of ANXA1 induces RGC apoptosis in a murine glaucoma model, and the maintenance of ANXA1 secreted in the extracellular environments remains unclear. In this study, we found that intravitreal injection of the recombinant adenovirus vector (Ad)-ATP-binding cassette tran ...[more]

PMID: 33665225

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Project description:BackgroundRetinal function is ordered by interactions between transcriptional and posttranscriptional regulators at the molecular level. These regulators include transcription factors (TFs) and posttranscriptional factors such as microRNAs (miRs). Some studies propose that miRs predominantly target the TFs rather than other types of protein coding genes and such studies suggest a possible interconnection of these two regulators in co-regulatory networks.ResultsOur lab has generated mRNA and miRNA microarray expression data to investigate time-dependent changes in gene expression, following induction of ischemia-reperfusion (IR) injury in the rat retina. Data from different reperfusion time points following retinal IR-injury were analyzed. Paired expression data for miRNA-target gene (TG), TF-TG, miRNA-TF were used to identify regulatory loop motifs whose expressions were altered by the IR injury paradigm. These loops were subsequently integrated into larger regulatory networks and biological functions were assayed. Systematic analyses of the networks have provided new insights into retinal gene regulation in the early and late periods of IR. We found both overlapping and unique patterns of molecular expression at the two time points. These patterns can be defined by their characteristic molecular motifs as well as their associated biological processes. We highlighted the regulatory elements of miRs and TFs associated with biological processes in the early and late phases of ischemia-reperfusion injury.ConclusionsThe etiology of retinal ischemia-reperfusion injury is orchestrated by complex and still not well understood gene networks. This work represents the first large network analysis to integrate miRNA and mRNA expression profiles in context of retinal ischemia. It is likely that an appreciation of such regulatory networks will have prognostic potential. In addition, the computational framework described in this study can be used to construct miRNA-TF interactive systems networks for various diseases/disorders of the retina and other tissues.

Dataset Information

Ad- and AAV8-mediated ABCA1 gene therapy in a murine model with retinal ischemia/reperfusion injuries.

Publications

Ad- and AAV8-mediated <i>ABCA1</i> gene therapy in a murine model with retinal ischemia/reperfusion injuries.

Similar Datasets

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