Targeting ATF6 Reduces Pathological Neovascularization and Improves Visual Outcomes in Retinal Disease Models
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PROVIDER: PRJNA1236858 | ENA |
REPOSITORIES: ENA
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Project description:Pathological retinal neovascularization is a common mechanism for leading causes of vision loss including retinopathy of prematurity (ROP), diabetic retinopathy, and wet age-related macular degeneration. The Unfolded Protein Response (UPR) is an intracellular signal transduction mechanism controlled by the ER-resident proteins ATF6, IRE1, and PERK. In response to endoplasmic reticulum stress, UPR activates downstream transcriptional and translational programs that upregulate many proteins, including key angiogenesis factors like VEGF and HIF1a. This suggests an important role for UPR in developmental and pathologic retinal angiogenesis, but it is unclear which UPR regulatory genes are most important in these processes. Here, we focused on the role of Activating Transcription Factor 6 (ATF6) in pathologic and developmental retinal angiogenesis. We induced pathologic retinal neovascularization in Atf6-/- mice using the oxygen-induced retinopathy (OIR) model of ROP and examined functional, histologic, and molecular consequences in the retina. we found significantly preserved visual function, accompanied by decreased retinal neovascularization, endothelial cell proliferation, and UPR and angiogenesis transcriptional programs in Atf6-/- mice after OIR. When we chemically blocked ATF6 signaling by intraocular injection of the small molecule Ceapin-A7, we also saw suppression of UPR and angiogenesis gene expression. Last, we examined very young Atf6-/- mice when the inner retinal vasculature is developing and found a significant defect in pruning and blood vessel extension to the periphery at P7, but this delay was transient and Atf6-/- blood vessels fully recovered at older ages of development. Together, our results demonstrate ATF6’s critical role in developmental and pathological angiogenesis and highlight its potential as a therapeutic target to mitigate pathological retinal neovascularization.
2025-08-14 | GSE292097 | GEO
Project description:Achromatopsia (ACHM) is an autosomal recessive disease that results in severe visual loss. Symptoms of ACHM include impaired visual acuity, nystagmus, and photoaversion starting from infancy; furthermore, ACHM is associated with bilateral foveal hypoplasia and absent or severely reduced cone photoreceptor function on electroretinography. Here, we performed genetic sequencing in 3 patients from 2 families with ACHM, identifying and functionally characterizing 2 mutations in the activating transcription factor 6 (ATF6) gene. We identified a homozygous deletion covering exons 8–14 of the ATF6 gene from 2 siblings from the same family. In another patient from a different family, we identified a heterozygous deletion covering exons 2 and 3 of the ATF6 gene found in trans with a previously identified ATF6 c.970C>T (p.Arg324Cys) ACHM disease allele. Recombinant ATF6 proteins bearing these exon deletions showed markedly impaired transcriptional activity by qPCR and RNA-Seq analysis compared with WT-ATF6. Finally, RNAscope revealed that ATF6 and the related ATF6B transcripts were expressed in cones as well as in all retinal layers in normal human retina. Overall, our data identify loss-of-function ATF6 disease alleles that cause human foveal disease.
2020-07-08 | GSE153978 | GEO
Project description:Roundabout (ROBO) 1 and 2 are transmembrane receptors that bind secreted SLIT ligands through their extracellular domains (ECD), and signal through their cytoplasmic domains to modulate the cytoskeleton and regulate cell migration, adhesion, and proliferation. SLIT-ROBO signaling was discovered as a guidance cue for axons in the developing nervous system, but ROBO receptors are expressed by many additional cell types and more broadly regulate organ morphogenesis, as well as cancer and pathological ocular neovascularization. As pharmacological tools to prevent SLIT-ROBOR signaling are lacking, herein we developed human monoclonal antibodies (mAb ) against the ROBO1 and 2 ECD. One antibody that inhibited in vitro SLIT2 signaling through ROBO1/2 reduced ocular neovascularization in two pathological models in vivo . Single cell RNA sequencing revealed that antibody treatment affected several cell types relevant to angiogenesis, including endothelial cells, pericytes, and a heterogeneous population of myeloid cells. mAb treatment improved Blood-Retina Barrier integrity and prevented pathological pericyte activation . SLIT-ROBO signaling inhibition prevented pathological activation of myeloid cells, which was phenocopied by both myeloid cell specific ablation of Robo1 and 2 and by knockout of the downstream effector Pi3kγ . Anti-ROBO1/2 blocking antibodies may thus provide a new promising strategy to combat inflammation in blinding eye diseases.
2024-12-03 | GSE279825 | GEO
Project description:Neovascularization contributes to multiple visual disorders including age-related macular degeneration (AMD). Current therapies for treating ocular angiogenesis are centered on the inhibition of vascular endothelial growth factor (VEGF). While clinically effective, some AMD patients are refractory or develop resistance to anti-VEGF and concerns of increased risks of developing geographic atrophy following long-term treatment have been raised. Identification of alternative pathways to inhibit pathological angiogenesis is thus important. We have identified a novel inhibitor of angiogenesis, COCO/DAND5, a member of the Cerberus-related DAN family. We demonstrate that COCO inhibits sprouting, migration and cellular proliferation of cultured endothelial cells. Intravitreal injections of COCO inhibited retinal vascularization during development and in models of retinopathy of prematurity and AMD. COCO equally abrogated angiogenesis in choroid explants and in a model of choroidal neovascularization. Mechanistically, COCO inhibited the expression of TGFβ and BMP pathwaysand altered ATP production, glucose uptake and redox balance of endothelial cells. Together, these data show that COCO is an inhibitor of retinal and choroidal angiogenesis, possibly representing a therapeutic option for the treatment of neovascular ocular diseases.
2020-12-22 | GSE160099 | GEO
Project description:ATF6 encodes a transcription factor that is activated during the Unfolded Protein Response to protect cells from ER stress. Loss of ATF6α and its paralog ATF6β, results in embryonic lethality, notochord dysgenesis, and in people, loss of ATF6α specifically, results in malformed neuroretina and congenital vision loss. These phenotypes implicate an essential role for ATF6 during vertebrate development. We investigated the function of ATF6 in development using human stem cells undergoing differentiation into multipotent germ layers, nascent tissues, and organs. We artificially activated ATF6 in stem cells with a recently identified small molecule ATF6 agonist, and we inhibited ATF6 using iPSCs from patients harboring ATF6 mutations. We discovered that ATF6 suppresses pluripotency, enhances differentiation, and surprisingly, guides stem cells toward mesodermal cell fates. Our findings reveal a novel role for ATF6 during differentiation and identify a new strategy to robustly create mesodermal tissues through modulation of the ATF6 arm of the UPR.
2017-11-14 | GSE106847 | GEO
Project description:The Unfolded Protein Response (UPR) maintains endoplasmic reticulum (ER) homeostasis and is essential for retinal health. Activating Transcription Factor 6 (ATF6) controls a key UPR branch and upregulates genes that mitigate ER stress. Small molecule modulators of ATF6 have been characterized in cell culture models that increase or decrease the amount of the cleaved, transcriptional activator domain of ATF6 generated from the full-length precursor. However, the effects of these small molecule ATF6 modulators remains unclear in vivo, in part because of the lack of antibodies that robustly detect the cleaved, activated form of ATF6 in model organisms like mice. Here, we used targeted RNA sequencing (RNA-seq) to assess the transcriptional response to intraocular delivery of Ceapin-A7 (an ATF6 inhibitor) and AA147 (an ATF6 activator) in the mouse retina. Using this strategy, we demonstrate that Ceapin-A7 significantly suppressed ATF6 transcriptional targets, whereas AA147 induced ATF6-regulated genes in retinal tissue of the eye. We also show that neither small molecule ATF6 modulator caused retinal cell death, compromised vision, or triggered ER stress by histology, functional testing, and transcriptional analysis. These results identify a transcriptional strategy to sensitively detect and quantify Ceapin-A7 and AA147 modulation of ATF6 in vivo. These findings also identify non-toxic conditions for further in vivo evaluation of small molecule ATF6 modulators in mouse vision loss disease models linked to ER stress.
2025-08-19 | GSE289701 | GEO
Project description:Pathological retinal angiogenesis with irregular and fragile vessels (also termed as neovascularization, a response to hypoxia and dysmetabolism) is a leading cause of vision loss in all age groups driven in part by unmet metabolic demand from retinal neurons. Sustaining neural retinal metabolism with an adequate nutrient supply may prevent vision-threatening neovascularization. Low circulating serine levels are associated with neovascularization in macular telangiectasia and altered serine/glycine metabolism is suggested in retinopathy of prematurity. Here we assessed the role of serine metabolism in suppressing hypoxia-driven retinal neovascularization in mice. Systemic serine supplementation decreased, and dietary serine/glycine deficiency worsened retinal neovascularization. Fatty acid oxidation was essential in mediating serine protective effects and serine also increased the levels of phosphatidylcholine, the most abundant phospholipids in the retina. Exogenous serine increased abundance of proteins involved in oxidative phosphorylation in total retinas, as well as increased expression of mitochondrial respiration-related genes and decreased expression of pro-angiogenic genes in rod photoreceptor cluster. Pharmaceutical inhibition of mitochondrial energy production largely attenuated serine suppression of retinal neovascularization. Our data suggested that increasing serine is a potential therapeutic approach for neovascular eye diseases by enhancing retinal mitochondrial function and lipid metabolism to suppress driving factors for uncontrolled angiogenesis.
2025-05-07 | PXD056490 | Pride
Project description:Corticotomy is a clinical procedure targeting alveolar bone to activate regional acceleratory phenomenon (RAP) and promote orthodontic tooth movement (OTM). Corticotomy involves the orchestration of inflammation by macrophages, but the underlying mechanism remains unclear. Here, we identify endoplasmic reticulum (ER) stress sensor activating transcription factor 6 (ATF6) as a critical player modulating pro- and anti-inflammatory macrophage polarization. We show that macrophage-specific ATF6 deletion blocks corticotomy-induced OTM acceleration, while macrophage ATF6 overexpression exaggerates the acceleration effect. Furthermore, the proportion of pro-inflammatory macrophages is positively correlated with ATF6 expression in vitro and in vivo. By RNA-seq and CUT&Tag, we demonstrate that ATF6 interacts with Tnfα promotor and augments its transcription, thereby mediating the effect of TNF signaling pathway in pro-inflammatory macrophage polarization. In summary, ATF6 may aggravate alveolar bone remodeling during corticotomy by promoting Tnfα transcription in macrophages, suggesting that ATF6 may represent a promising therapeutic target for non-invasive accelerating orthodontics.
2025-04-09 | GSE246048 | GEO
Project description:Corticotomy is a clinical procedure targeting alveolar bone to activate regional acceleratory phenomenon (RAP) and promote orthodontic tooth movement (OTM). Corticotomy involves the orchestration of inflammation by macrophages, but the underlying mechanism remains unclear. Here, we identify endoplasmic reticulum (ER) stress sensor activating transcription factor 6 (ATF6) as a critical player modulating pro- and anti-inflammatory macrophage polarization. We show that macrophage-specific ATF6 deletion blocks corticotomy-induced OTM acceleration, while macrophage ATF6 overexpression exaggerates the acceleration effect. Furthermore, the proportion of pro-inflammatory macrophages is positively correlated with ATF6 expression in vitro and in vivo. By RNA-seq and CUT&Tag, we demonstrate that ATF6 interacts with Tnfα promotor and augments its transcription, thereby mediating the effect of TNF signaling pathway in pro-inflammatory macrophage polarization. In summary, ATF6 may aggravate alveolar bone remodeling during corticotomy by promoting Tnfα transcription in macrophages, suggesting that ATF6 may represent a promising therapeutic target for non-invasive accelerating orthodontics.
2025-04-09 | GSE245975 | GEO
Project description:Monoclonal antibodies that block Roundabout 1 and 2 signaling target pathological ocular neovascularization through myeloid cells
| PRJNA1174746 | ENA