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- Li, Shasha, et al.
(författare)
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A systems genetics approach to revealing the Pdgfb molecular network of the retina
- 2020
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Ingår i: Molecular Vision. - : MOLECULAR VISION. - 1090-0535. ; 26, s. 459-471
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Platelet-derived growth factor (PDGF) signaling is well known to be involved in vascular retinopathies. Among the PDGF family, the subunit B (PDGFB) protein is considered a promising therapeutic target. This study aimed to identify the genes and potential pathways through which PDGFB affects retinal phenotypes by using a systems genetics approach. Methods: Gene expression data had been previously generated in a laboratory for the retinas of 75 C57BL/6J(B6) X DBA/2J (BXD) recombinant inbred (RI) strains. Using this data, the genetic correlation method was used to identify genes correlated to Pdgfb. A correlation between intraocular pressure (TOP) and Pdgfb was calculated based on the Pearson correlation coefficient. A gene set enrichment analysis and the STRING database were used to evaluate gene function and to construct protein-protein interaction (PPI) networks. Results: Pdgfb was a cis-regulated gene in the retina; its expression had a significant correlation with IOP (r = 0.305; p value = 0.012). The expression levels of 2,477 genes also had significant correlations with Pdgfb expressions (p<0.05), among which Atf4 was the most positively correlated (r = 0.628; p value = 1.29e-10). Thus, Atf4 was highly expressed in the retina and shared the transcription factor (TF)Hnf4a binding site with Pdgfb. Gene Ontology and a pathway analysis revealed that Pdgfb and its covariates were highly involved in mitogen-activated protein kinase (MAPK) and vascular endothelial growth factor (VEGF) pathways. A generated gene network indicated that Pdgfb was directly connected to and interacted with other genes with similar biologic functions. Conclusions: A systems genetics analysis revealed that Pdgfb had significant interactions with Atf4 and other genes in MAPK and VEGF pathways, through which Pdgfb was important in maintaining retina function. These findings provided basic information regarding the Pdgfb regulation mechanism and potential therapy for vascular retinopathies.
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| 2. |
- Ali, Zaheer, et al.
(författare)
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Synchronized tissue-scale vasculogenesis and ubiquitous lateral sprouting underlie the unique architecture of the choriocapillaris
- 2020
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Ingår i: Developmental Biology. - : ACADEMIC PRESS INC ELSEVIER SCIENCE. - 0012-1606 .- 1095-564X. ; 457:2, s. 206-214
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Tidskriftsartikel (refereegranskat)abstract
- The choriocapillaris is an exceptionally high density, two-dimensional, sheet-like capillary network, characterized by the highest exchange rate of nutrients for waste products per area in the organism. These unique morphological and physiological features are critical for supporting the extreme metabolic requirements of the outer retina needed for vision. The developmental mechanisms and processes responsible for generating this unique vascular network remain, however, poorly understood. Here we take advantage of the zebrafish as a model organism for gaining novel insights into the cellular dynamics and molecular signaling mechanisms involved in the development of the choriocapillaris. We show for the first time that zebrafish have a choriocapillaris highly similar to that in mammals, and that it is initially formed by a novel process of synchronized vasculogenesis occurring simultaneously across the entire outer retina. This initial vascular network expands by un-inhibited sprouting angiogenesis whereby all endothelial cells adopt tip-cell characteristics, a process which is sustained throughout embryonic and early post-natal development, even after the choriocapillaris becomes perfused. Ubiquitous sprouting was maintained by continuous VEGF-VEGFR2 signaling in endothelial cells delaying maturation until immediately before stages where vision becomes important for survival, leading to the unparalleled high density and lobular structure of this vasculature. Sprouting was throughout development limited to two dimensions by Bruchs membrane and the sclera at the anterior and posterior surfaces respectively. These novel cellular and molecular mechanisms underlying choriocapillaris development were recapitulated in mice. In conclusion, our findings reveal novel mechanisms underlying the development of the choriocapillaris during zebrafish and mouse development. These results may explain the uniquely high density and sheet-like organization of this vasculature.
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