13 results on '"Dillinger, Andrea E."'
Search Results
2. CCN2/CTGF promotor activity in the developing and adult mouse eye
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Dillinger, Andrea E., Kuespert, Sabrina, Froemel, Franziska, Tamm, Ernst R., and Fuchshofer, Rudolf
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- 2021
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3. CCN2/CTGF—A Modulator of the Optic Nerve Head Astrocyte
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Dillinger, Andrea E., Weber, Gregor R., Mayer, Matthias, Schneider, Magdalena, Göppner, Corinna, Ohlmann, Andreas, Shamonin, Mikhail, Monkman, Gareth J., and Fuchshofer, Rudolf
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ddc:610 ,genetic structures ,integumentary system ,610 Medizin ,glaucoma, optic nerve, growth factors, astrocytes, stiffness, extracellar matrix, glial lamina ,sense organs ,Cell Biology ,eye diseases ,Developmental Biology - Abstract
In primary open-angle glaucoma (POAG), a neurodegenerative disease of the optic nerve (ON) and leading cause of blindness, the optic nerve head (ONH) undergoes marked structural extracellular matrix (ECM) changes, which contribute to its permanent deformation and to degeneration of ON axons. The remodeling process of the ECM causes changes in the biomechanical properties of the ONH and the peripapillary sclera, which is accompanied by an increased reactivity of the resident astrocytes. The molecular factors involved in the remodeling process belong to the Transforming growth factor (TGF)-β superfamily, especially TGF-β2. In previous publications we showed that TGF-β2 induced ECM alterations are mediated by Cellular Communication Network Factor (CCN)2/Connective Tissue Growth Factor (CTGF) and recently we showed that CCN2/CTGF is expressed by astrocytes of the ON under normal conditions. In this study we wanted to get a better understanding of the function of CCN2/CTGF under normal and pathologic conditions. To this end, we analyzed the glial lamina and peripapillary sclera of CCN2/CTGF overexpressing mice and studied the effect of CCN2/CTGF and increasing substratum stiffness on murine ON astrocytes in vitro. We observed enhanced astrocyte reactivity in the ONH, increased ECM protein synthesis in the peripapillary sclera and increased Ccn2/Ctgf expression in the ONH during the pathologic development in situ. CCN2/CTGF treatment of primary murine ON astrocytes induced a higher migration rate, and increase of ECM proteins including fibronectin, elastin and collagen type III. Furthermore, the astrocytes responded to stiffer substratum with increased glial fibrillary acidic protein, vimentin, actin and CCN2/CTGF synthesis. Finally, we observed the reinforced appearance of CCN2/CTGF in the lamina cribrosa of glaucomatous patients. We conclude that reactive changes in ONH astrocytes, induced by the altered biomechanical characteristics of the region, give rise to a self-amplifying process that includes increased TGF-β2/CCN2/CTGF signaling and leads to the synthesis of ECM molecules and cytoskeleton proteins, a process that in turn augments the stiffness at the ONH. Such a scenario may finally result in a vicious circle in the pathogenesis of POAG. The transgenic CTGF-overexpressing mouse model might be an optimal model to study the chronic pathological POAG changes in the ONH.
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- 2022
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4. Targeted drug delivery to the retinal pigment epithelium: Untapped therapeutic potential for retinal diseases.
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Bohley, Marilena, Dillinger, Andrea E., Tamm, Ernst R., and Goepferich, Achim
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RETINAL diseases , *TARGETED drug delivery , *RHODOPSIN , *MACULAR degeneration , *DIABETIC retinopathy , *EPITHELIUM - Abstract
• Most retinal diseases underly multifactorial pathomechanisms. • The retinal pigment epithelium (RPE) plays a key part in these pathomechanisms. • Targeted RPE therapy can be used to efficiently treat retinal diseases. • Intravitreal and systemic nanoparticle systems can reach the RPE. • Guidance for the development of RPE-specific nanotherapeutics is provided. The retinal pigment epithelium (RPE) plays a crucial part in sight-threatening diseases. In this review, we shed light on the pivotal implication of the RPE in age-related macular degeneration, diabetic retinopathy and retinopathy of prematurity; and explain why a paradigm shift toward targeted RPE therapy is needed to efficiently fight these retinal diseases. We provide guidance for the development of RPE-specific nanotherapeutics by giving a comprehensive overview of the possibilities and challenges of drug delivery to the RPE and highlight successful nanotherapeutic approaches targeting the RPE. [ABSTRACT FROM AUTHOR]
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- 2022
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5. Involvement of CTGF in eye development and the pathology of glaucoma
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Dillinger, Andrea E.
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eye development, glaucoma, astrocytes, nanoparticles ,integumentary system ,genetic structures ,570 Biowissenschaften, Biologie ,sense organs ,ddc:570 ,eye diseases - Abstract
Primary open angle glaucoma, a neurodegenerative disease of the optic nerve (ON), is one of the leading cause of blindness worldwide (Quigley 1996). In progression of the disease the optic nerve head (ONH) undergoes marked structural extracellular matrix changes (ECM), which lead to its permanent deformation and can contribute to the degeneration of ON axons. The changes in ECM in the ONH correlate with an increased reactivity of astrocytes. An intraocular pressure (IOP), which is too high for the health of the ON axons, was identified as the major risk factor for the development for the POAG (Collaborative-Normal-Tension-Glaucoma-Study-Group, 1998; The AGIS Investigators2000; Gordon et al. 2002; Lichter et al., 2001; Johnson et al., 2002; Kass et al. 2002; Leske et al., 2003). In POAG the homeostatic balance of different growth factors, affecting the resistance of the outflow pathway is altered (Inatani et al. 2001, Min et al. 2006, Ochiai & Ochiai 2002, Ozcan et al. 2004, Picht et al. 2001, Tripathi et al. 1994, Trivedi et al. 2011). In the last years, the Connective Tissue Growth Factor (CTGF) came into focus as a lens-specific overexpression of CTGF in the mice results in an elevated IOP and a significant progressive loss of retinal ganglion cell (RGC) axons over time (Junglas et al., 2012). CTGF is a member of matricellular regulatory proteins and downstream mediator of Transforming Growth Factor β2, and is involved in many different functions, like migration, adhesion, differentiation and ECM production. By its modular organization CTGF can arrange various interactions with different growth factors, integrins and ECM proteins. In this study we investigated the involvement of CTGF during eye development and the pathology of POAG. The effect of alterations in substratum stiffness on an increased astrocyte reactivity and the implication of possible mechanosensors was analyzed. The final aspect of the study was to develop siRNA coated NP for specific delivery to the AH outflow pathway tissue and cells. During eye development CTGF is expressed in various eye structures. In early embryonic development an expression in the outer and inner layer of the optic cup as well as the lens vesicle was observed. In the following embryonic and postnatal developmental stages, CTGF expression was detected in tissues of the anterior eye segment like corneal endothelium, epithelium and stroma, in the TM and ciliary body. In the posterior eye segment an expression could be found in the retina, choroidea, sclera, ONH and dura mater. During the development of the eye CTGF expression showed tissue specific changes in the cornea, the ciliary body, the retina, the ONH and the dura mater, whereas the expression the TM remained constantly high. The characterization of the CTGF expressing cells types revealed that the trabecular meshwork cells, Müller cells, amacrine cells, ON astrocytes and endothelial cells of the SC and of the retinal and choroidal vasculature, were the source of the CTGF signal. An important role for CTGF in the correct formation of astrocytic morphology in the retina and the ONH could be shown in CTGF conditional knockdown mice. Beside the involvement of CTGF in developmental processes a correlation between CTGF expression and pathological changes in the murine glaucoma model was observed. An increased astrocyte reactivity was associated with an enhanced CTGF synthesis in the ONH related to the chronic elevated IOP, whereas none of those changes were observed in the adjacent parts of the ON. Interestingly, cultured murine ON astrocytes could sense changes in stiffness of the surrounding ECM causing the same changes like in the in vivo glaucoma model. The analysis of mechanosensitive ion channels showed a broad spectrum of expression changes dependent on the substratum stiffness, but the most promising changes were seen in Caveolin expression. An enhanced Caveolin synthesis in ON astrocytes was detected on increasing substratum stiffness and after treatment with CTGF and TGF-β2 in vitro and in the ONH of the murine glaucoma model. Layer-by-layer coated NPs were designed and successfully delivered by anterior chamber perfusion to the outflow pathway tissues of porcine and human eyes. CD44 was identified as an ideal target for HA coated NPs, as CD44 is permanently present in cultured HTM cells, in the anterior chamber angle of murine and human donor eyes. The implication of CD44 in POAG could be shown by the enhanced expression in glaucomatous SC cells and the anterior chamber angle of human glaucomatous donor eyes. Finally, siRNA coated NP’s could successfully reduce CTGF synthesis in HTM cells in vitro. We observed that CTGF is highly expressed in various ocular structures and we conclude that CTGF plays an essential role in the formation of astrocyte structures during development. Further we state that astrocyte reactivity induced by increasing stiffness of their surrounding matrix lead to increased levels of CTGF, which in turn contribute to the changes in ECM observed in POAG. Furthermore, the results of this study indicate that siRNA delivery to the AH outflow pathway tissue and cells based on HA-coated NPs could have a great potential in treatment of POAG., Das Primäre Offenwinkelglaukom (POWG), eine neurodegenerative Erkrankung des Sehnervens, ist eine der häufigsten Erblindungsursachen weltweit (Quigley, 1996). Im Verlauf der Erkrankung kommt es zu starken strukturellen Veränderungen der extrazellulären Matrix (EZM), welche zu einer permanenten Deformation des Sehnervenkopfes führt. Infolgedessen kommt es zu einer Degeneration der Axone im Bereich des Sehnervenkopfes. Die Veränderungen der EZM im Sehnervenkopf geht einher mit einer erhöhten Reaktivität der Astrozyten. Der intraokuläre Druck (IOD) konnte in randomisierten, klinischen Multicenter Studien als ein Hauptrisikofaktor für die Erkrankung des POWGs identifiziert werden (Collaborative-Normal-Tension-Glaucoma-Study-Group, 1998; The AGIS Investigators2000; Gordon et al. 2002; Lichter et al., 2001; Johnson et al., 2002; Kass et al. 2002; Leske et al., 2003). Im POWG ist die Balance zwischen einigen Wachstumsfaktoren, welche den Ausflusswiderstand im Trabekelwerk und Schlemmschen Kanal (SK) beeinflussen verändert (Inatani et al. 2001, Min et al. 2006, Ochiai & Ochiai 2002, Ozcan et al. 2004, Picht et al. 2001, Tripathi et al. 1994, Trivedi et al. 2011). In den letzten Jahren rückte der Wachstumsfaktor Connective Tissue Growth Factor (CTGF) immer mehr in den Fokus, da in dem Mausmodell mit einer linsen-spezifischen Überexpression von CTGF ein erhöhter IOD und ein signifikanter, progressiver Verlust der Axone der retinalen Ganglienzellen festgestellt wurde. CTGF ist ein sezerniertes, matrizelluläres Glykoprotein und fungiert als downstream Mediator des Wachstumsfaktors Transforming Growth Factor-β2 (TGF-β2). Die Beteiligung von CTGF an unterschiedlichen Prozessen wie Migration, Adhesion, Differenzierung und EZM-Produktion wurde bereits in verschiedenen Zelltypen identifiziert, des Weiteren kann dieser Wachstumsfaktor durch seine modulare Struktur verschiedene Interaktionen mit unterschiedlichen Wachstumsfaktoren, Integrinen und EZM Proteinen eingehen. In dieser Arbeit wurde die Beteiligung von CTGF während der Augenentwicklung und der Pathologie des POWGs untersucht. Der Effekt von erhöhter Substratrigidität auf die Reaktivität von Astrozyten und die mögliche Beteiligung von Mechanosensoren wurde überprüft. Der finale Aspekt dieser Arbeit war es, siRNA beschichtete Nanopartikel zur Applikation in die Gewebe des Kammerwasserabflussweges herzustellen. Während der Augenentwicklung ist CTGF in verschiedenen Augenstrukturen exprimiert. Während der frühen Embryonalentwicklung konnte eine Expression in der äußeren und inneren Schicht des Augenbechers, so wie im Linsenbläschen festgestellt werden. In den folgenden embryonalen und postnatalen Entwicklungsstadien wurde eine CTGF Expression in Geweben der vorderen Augenkammer wie Endothelium, Epithelium und Stroma der Kornea, im Trabekelwerk und dem Ziliarkörper nachgewiesen. In der hinteren Augenkammer konnte eine CTGF Expression in der Retina, der Choroidea, der Sklera, dem Sehnerv und der Dura mater festgestellt werden. Im Verlauf der Entwicklung kommt es zu Veränderungen im Expressionmuster von CTGF in der Kornea, dem Ziliarkörper, der Retina, dem Sehnerv und der Dura mater. Im Gegensatz dazu blieb die Expression im Trabekelwerk konstant hoch. Durch die Charakterisierung der CTGF-exprimierenden Zelltypen, zeigten sich Trabekelwerkzellen, Müller Zellen, Amakrinzellen, Sehnervenastrozyten und Endothelzellen des SKs und der retinalen und choroidalen Gefäße als die Quelle der CTGF Expression. Durch die Analyse von konditionellen CTGF Knockout Mäusen konnte die wichtige Rolle von CTGF bei der Ausbildung der korrekten Astrozyten-Morphologie während der Augenentwicklung gezeigt werden. Neben der Beteiligung von CTGF in Entwicklungsprozessen wurde die Korrelation der CTGF Expression und den pathologischen Veränderungen im Sehnerv an einem Glaukom-Mausmodell untersucht. Hierbei konnte in Bezug auf den chronisch erhöhten IOD eine erhöhte Astrozyten Reaktivität mit einer vermehrten CTGF Synthese im Sehnervenkopf assoziiert werden. Im Vergleich dazu konnte im angrenzenden Sehnerv keinerlei derartige Veränderung beobachtet werden. Interessanterweise konnte in Zellkulturexperimenten festgestellt werden, dass Sehnervenastrozyten Unterschiede in der Rigidität der sie umgebenden Martix aufnehmen können und dies zu vergleichbaren Veränderung, wie sie im Mausmodell beobachtet wurden, führt. Die Analyse mechanosensitiver Ionenkanäle zeigte ein breites Spektrum an Expressionsunterschieden, abhängig von der Rigidität der Substrate. Den vielversprechendsten Unterschied in der Expression zeigte hierbei Caveolin. Eine erhöhte Expression von Caveolin konnte bei erhöhter Rigidität des Substrates, nach der Behandlung mit CTGF und TGF-β2 und im Sehnervenkopf des Glaukom-Mausmodells festgestellt werden. Im Rahmen dieser Arbeit konnten layer-by-layer Nanopatrikel erfolgreich durch eine Perfusion der vorderen Augenkammer von menschlichen Augen und Schweineauge in die Kammerwasserabflussgewebe eingebracht werden. Durch den Nachweis der permanenten Expression von CD44 in kultivierten humanen Trabekelwerkszellen und im Kammerwinkel von Mausaugen und humanen Augen, konnte CD44 als ein ideales Target für mit Hyaluronsäure beschichtet Nanopartikel identifiziert werden. Auch die Beteilung von CD44 in der Pathologie des POWG, zeigte sich durch eine Erhöhung von CD44 in glaukomatösen Zellen des SKs und im Kammerwinkel von menschlichen glaukomatösen Spenderaugen. Schließlich konnte die CTGF Synthese in humanen Trabekelwerkszellen erfolgreich durch siRNA beschichtete Nanopartikel reduziert werden. Im Rahmen dieser Arbeit konnte eine starke Expression von CTGF in verschiedenen Augenstrukturen nachgewiesen werden. Weiterhin konnte eine Rolle von CTGF bei der Ausbildung der Astrozyten-Morphologie während der Augenentwicklung festgestellt werden. Des Weiteren stellten wir fest, dass durch eine erhöhte Rigidität des Substrates eine Astrozyten Reaktivität induziert wird, welche schließlich zu einer Erhöhung an CTGF führt. Darüber hinaus zeigten die Ergebnisse dieser Arbeit das deutliche Potential von Hyaluronsäure-beschichter Nanopartikel zur Einbringung von siRNA in das Kammerwasserabflussgewebe als eine Behandlungsmöglichkeit des POWGs.
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- 2019
6. Intracameral Delivery of Layer‐by‐Layer Coated siRNA Nanoparticles for Glaucoma Therapy.
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Dillinger, Andrea E., Guter, Michaela, Froemel, Franziska, Weber, Gregor R., Perkumas, Kristin, Stamer, W. Daniel, Ohlmann, Andreas, Fuchshofer, Rudolf, and Breunig, Miriam
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- 2018
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7. Decorin—An Antagonist of TGF-β in Astrocytes of the Optic Nerve.
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Schneider, Magdalena, Dillinger, Andrea E., Ohlmann, Andreas, Iozzo, Renato V., and Fuchshofer, Rudolf
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OPTIC nerve , *CONNECTIVE tissue growth factor , *ASTROCYTES , *PROTEIN kinase B , *TRANSFORMING growth factors - Abstract
During the pathogenesis of glaucoma, optic nerve (ON) axons become continuously damaged at the optic nerve head (ONH). This often is associated with reactive astrocytes and increased transforming growth factor (TGF-β) 2 levels. In this study we tested the hypothesis if the presence or absence of decorin (DCN), a small leucine-rich proteoglycan and a natural inhibitor of several members of the TGF family, would affect the expression of the TGF-βs and connective tissue growth factor (CTGF/CCN2) in human ONH astrocytes and murine ON astrocytes. We found that DCN is present in the mouse ON and is expressed by human ONH and murine ON astrocytes. DCN expression and synthesis was significantly reduced after 24 h treatment with 3 nM CTGF/CCN2, while treatment with 4 pM TGF-β2 only reduced expression of DCN significantly. Conversely, DCN treatment significantly reduced the expression of TGF-β1, TGF-β2 and CTGF/CCN2 vis-a-vis untreated controls. Furthermore, DCN treatment significantly reduced expression of fibronectin (FN) and collagen IV (COL IV). Notably, combined treatment with DCN and triciribine, a small molecule inhibitor of protein kinase B (AKT), attenuated effects of DCN on CTGF/CCN2, TGF-β1, and TGF-β2 mRNA expression. We conclude (1) that DCN is an important regulator of TGF-β and CTGF/CCN2 expression in astrocytes of the ON and ONH, (2) that DCN thereby regulates the expression of extracellular matrix (ECM) components and (3) that DCN executes its negative regulatory effects on TGF-β and CTGF/CCN2 via the pAKT/AKT signaling pathway in ON astrocytes. [ABSTRACT FROM AUTHOR]
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- 2021
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8. A novel ocular function for decorin in the aqueous humor outflow.
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Schneider, Magdalena, Pawlak, Ramona, Weber, Gregor R., Dillinger, Andrea E., Kuespert, Sabrina, Iozzo, Renato V., Quigley, Harry A., Ohlmann, Andreas, Tamm, Ernst R., and Fuchshofer, Rudolf
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TRABECULAR meshwork (Eye) , *AQUEOUS humor , *INTRAOCULAR pressure , *OPEN-angle glaucoma , *TRANSFORMING growth factors , *AXONS - Abstract
• Decorin deficiency leads to elevated intraocular pressure in mice. • TGF-β target genes are enriched in the conventional outflow pathways of decorin-deficient mice. • Decorin attenuates the expression of TGF-β2 in cultured HTM cells. • Decorin levels are reduced in the chamber angle of glaucomatous eyes. Primary open-angle glaucoma, a neurodegenerative disorder characterized by degeneration of optic nerve axons, is a frequent cause of vision loss and blindness worldwide. Several randomized multicenter studies have identified intraocular pressure as the major risk factor for its development, caused by an increased outflow resistance to the aqueous humor within the trabecular meshwork. However, the molecular mechanism for increased outflow resistance in POAG has not been fully established. One of the proposed players is the pro-fibrotic transforming growth factor (TGF)-β2, which is found in higher amounts in the aqueous humor of patients with POAG. In this study we elucidated the role of decorin, a small leucine-rich proteoglycan and known antagonist of TGF-β, in the region of aqueous humor outflow tissue. Utilizing decorin deficient mice, we discovered that decorin modulated TGF-β signaling in the canonical outflow pathways and the lack of decorin in vivo caused an increase in intraocular pressure. Additionally, the Dcn −/− mice showed significant loss of optic nerve axons and morphological changes in the glial lamina, typical features of glaucoma. Moreover, using human trabecular meshwork cells we discovered that soluble decorin attenuated TGF-β2 mediated synthesis and expression of typical downstream target genes including CCN2/CTGF, FN and COL IV. Finally, we found a negative reciprocal regulation of decorin and TGF-β, with a dramatic downregulation of decorin in the canonical outflow pathways of patients with primary open-angle glaucoma. Collectively, our results indicate that decorin plays an important role in the pathogenesis of primary open-angle glaucoma and offers novel perspectives in the treatment of this serious disease. [ABSTRACT FROM AUTHOR]
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- 2021
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9. Design of dye and superparamagnetic iron oxide nanoparticle loaded lipid nanocapsules with dual detectability in vitro and in vivo.
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Bohley, Marilena S., Birch, Emily, Baumann, Felix J., Dillinger, Andrea E., Tamm, Ernst R., and Goepferich, Achim M.
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NANOCAPSULES , *INDUCTIVELY coupled plasma atomic emission spectrometry , *FERRIC oxide , *IRON oxide nanoparticles , *IRON oxides - Abstract
Lipid nanocapsules are treasured nanoparticulate systems, although they lack detectability in biological environments. To overcome this, we designed LNCs loaded simultaneously with fluorescent dye and superparamagnetic iron oxide nanoparticles (Dual LNCs). The introduction of both labels did not alter nanoparticle characteristics such as size (50 nm), size distribution (polydispersity index < 0.1) or surface modifications, including the effectiveness of targeting ligands. Furthermore, the colloidal stability, particle integrity and biocompatibility of the nanoparticles were not negatively affected by label incorporation. These Dual LNCs are concomitantly visualizable via fluorescence and transmitted light imaging after either the internalization by cells or systemic administration to mice. Importantly, they are detectable in liver sections of mice using transmission electron microscopy without additional enhancement. The iron content of 0.24% (m/m) is sufficiently high for precise quantification of nanoparticle concentrations via inductively coupled plasma optical emission spectroscopy. Dual LNCs are precious tools for the investigation of in vitro and in vivo performances of lipid nanocapsule formulations, since they allow for the use of complementary imaging methods for broad range detectability. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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10. Induced Attenuation of Scleral TGF-β Signaling in Mutant Mice Increases Susceptibility to IOP-Induced Optic Nerve Damage.
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Gebert M, Heimbucher J, Gsell VK, Keimer K, Dillinger AE, and Tamm ER
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- Animals, Mice, Sclera, Tamoxifen, Transforming Growth Factor beta genetics, Optic Disk, Glaucoma, Optic Nerve Injuries
- Abstract
Purpose: Axonal optic nerve (ON) damage in glaucoma is characteristically associated with increased amounts of active transforming growth factor-beta 2 (TGF-β2) in the ON head. Here we investigated the functional role of scleral TGF-β signaling in glaucoma., Methods: A deficiency of Tgfbr2, which encodes for TGF-β receptor type II (TGF-βRII), the essential receptor for canonical TGF-β signaling, was induced in fibroblasts (including those of the sclera) of mutant mice. To this end, 5-week-old mice were treated with tamoxifen eye drops. Experimental glaucoma was induced in 8-week-old mice using a magnetic microbead (MB) model. After 6 weeks of high intraocular pressure (IOP), the ON axons and their somata in the retina were labeled by paraphenylenediamine (PPD) and RNA-binding protein with multiple splicing (RBPMS) immunohistochemistry, respectively, and quantified., Results: Tamoxifen treatment resulted in a significant decrease of TGF-βRII and its mRNA in the sclera. After 6 weeks of high IOP, reduced numbers of PPD-stained ON axons were seen in MB-injected eyes in comparison with not-injected contralateral eyes. Moreover, MB injection also led to a decrease of retinal ganglion cell (RGC) somata as seen in RBPMS-stained retinal wholemounts. Axon loss and RGC loss were significantly higher in mice with a fibroblast specific deficiency of TGF-βRII in comparison with control animals., Conclusions: We conclude that the ablation of scleral TGF-β signaling increases the susceptibility to IOP-induced ON damage. Scleral TGF-β signaling in mutant mice appears to be beneficial for ON axon survival in experimentally induced glaucoma.
- Published
- 2024
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11. CCN2/CTGF tip the balance of growth factors towards TGF-β2 in primary open-angle glaucoma.
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Dillinger AE, Kuespert S, Seleem AA, Neuendorf J, Schneider M, and Fuchshofer R
- Abstract
TGF-β2 is the predominant TGF-β isoform within the eye. One function of TGF-β2 is to provide the eye with immune protection against intraocular inflammation. The beneficial function of TGF-β2 within the eye must be under tight control of a network of different factors. A disbalance of the network can result in different eye diseases. In Primary Open-Angle Glaucoma (POAG), one of the leading causes of irreversible blindness worldwide, TGF-β2 is significantly elevated in the aqueous humor and antagonistic molecules like BMPs are reduced. The changes provoke an altering of the quantity and quality of the extracellular matrix and the actin cytoskeleton in the outflow tissues, leading to an increased outflow resistance and thereby to an increased intraocular pressure (IOP), the major risk factor for primary open-angle glaucoma. The pathologic effect of TGF-β2 in primary open-angle glaucoma is mainly meditated by CCN2/CTGF. CCN2/CTGF can modulate TGF-β and BMP signaling by direct binding. The eye specific overexpression of CCN2/CTGF caused an increase in IOP and led to a loss of axons, the hallmark of primary open-angle glaucoma. CCN2/CTGF appears to play a critical role in the homeostatic balance of the eye, so we investigated if CCN2/CTGF can modulate BMP and TGF-β signaling pathways in the outflow tissues. To this end, we analyzed the direct effect of CCN2/CTGF on both signaling pathways in two transgenic mouse models with a moderate (βB1-CTGF1) and a high CCN2/CTGF (βB1-CTGF6) overexpression and in immortalized human trabecular meshwork (HTM) cells. Additionally, we investigate whether CCN2/CTGF mediates TGF-β effects via different pathways. We observed developmental malformations in the ciliary body in βB1-CTGF6 caused by an inhibition of the BMP signaling pathway. In βB1-CTGF1, we detected a dysregulation of the BMP and TGF-β signaling pathways, with reduced BMP activity and increased TGF-β signaling. A direct CCN2/CTGF effect on BMP and TGF-β signaling was shown in immortalized HTM cells. Finally, CCN2/CTGF mediated its effects on TGF-β via the RhoA/ROCK and ERK signaling in immortalized HTM cells. We conclude that CCN2/CTGF functions as a modulator of the homeostatic balance of BMP and TGF-β signaling pathways, which is shifted in primary open-angle glaucoma., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Dillinger, Kuespert, Seleem, Neuendorf, Schneider and Fuchshofer.)
- Published
- 2023
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12. Retinal Pigmented Epithelium-Derived Ectopic Norrin Does Not Promote Intraretinal Angiogenesis in Transgenic Mice.
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Dillinger AE and Tamm ER
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- Mice, Animals, Mice, Transgenic, Retinal Pigment Epithelium metabolism, Epithelium, Eye Proteins physiology, beta Catenin genetics, beta Catenin metabolism, Retina metabolism
- Abstract
Formation of intraretinal capillaries and inner blood-retinal barrier during development requires norrin, a ligand of the canonical wingless/integrated (Wnt)/β-catenin signaling pathway. Here we addressed the question whether retinal pigmented epithelium (RPE)-derived overexpression of norrin in transgenic mice rescues the vascular phenotype caused by norrin deficiency. To this end, we generated Ndp
KO /Rpe65-Norrin mice and analyzed the activation of β-catenin signaling, the development of intraretinal capillaries, and the expression of blood-retinal barrier marker molecules. RPE-derived norrin induced retinal β-catenin signaling but failed to rescue the vascular developmental defects and the breakdown of the blood-retinal barrier in norrin-deficient mice. Sites of ectopic norrin expression and the amounts of secreted transgenic protein are critical factors to enable the angiogenic properties of norrin., (© 2023. The Author(s), under exclusive license to Springer Nature Switzerland AG.)- Published
- 2023
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13. A single intravenous injection of cyclosporin A-loaded lipid nanocapsules prevents retinopathy of prematurity.
- Author
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Bohley M, Dillinger AE, Schweda F, Ohlmann A, Braunger BM, Tamm ER, and Goepferich A
- Subjects
- Animals, Cyclosporine pharmacology, Cyclosporine therapeutic use, Humans, Infant, Newborn, Inflammation drug therapy, Injections, Intravenous, Lipids, Mice, Vascular Endothelial Growth Factor A, Nanocapsules therapeutic use, Retinopathy of Prematurity drug therapy, Retinopathy of Prematurity prevention & control
- Abstract
Retinopathy of prematurity (ROP) is a retinal disease that threatens the vision of prematurely born infants. Severe visual impairment up to complete blindness is caused by neovascularization and inflammation, progressively destroying the immature retina. ROP primarily affects newborns in middle- and low-income countries with limited access to current standard treatments such as intraocular drug injections and laser- or cryotherapy. To overcome these limitations, we developed a nanotherapeutic that effectively prevents ROP development with one simple intravenous injection. Its lipid nanocapsules transport the antiangiogenic and anti-inflammatory cyclosporin A efficiently into disease-driving retinal pigment epithelium cells. In a mouse model of ROP, a single intravenous injection of the nanotherapeutic prevented ROP and led to normal retinal development by counteracting neovascularization and inflammation. This nanotherapeutic approach has the potential to bring about a change of paradigm in ROP therapy and prevent millions of preterm born infants from developing ROP.
- Published
- 2022
- Full Text
- View/download PDF
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