Cotugno, Gabriella (2009) Inhibition of the Sonic Hedgehog pathway as a strategy to treat ocular neovascularization in animal models. [Tesi di dottorato] (Unpublished)
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| Item Type: | Tesi di dottorato |
|---|---|
| Resource language: | English |
| Title: | Inhibition of the Sonic Hedgehog pathway as a strategy to treat ocular neovascularization in animal models |
| Creators: | Creators Email Cotugno, Gabriella cotugno@tigem.it |
| Date: | 2009 |
| Number of Pages: | 153 |
| Institution: | Università degli Studi di Napoli Federico II |
| Istituzioni (extra): | CEINGE Biotecnologie Avanzate, TIGEM – Telethon Insitute of Genetics and Medicine |
| Department: | Telethon Institute of Genetics and Medicine (TIGEM) |
| Scuola di dottorato: | SEMM – European School of Molecular Medicine |
| Dottorato: | PhD in Molecular Medicine (Molecular Oncology or Human Genetics) |
| Ciclo di dottorato: | 20 |
| Coordinatore del Corso di dottorato: | nome email Salvatore, Francesco salvator@unina.it |
| Tutor: | nome email Auricchio, Alberto auricchio@tigem.it Pastore, Lucio pastore@ceinge.unina.it Ali, Robin r.ali@ucl.ac.uk |
| Date: | 2009 |
| Number of Pages: | 153 |
| Keywords: | Ocular Neovascularization, Diabetes, Gene Transfer |
| Settori scientifico-disciplinari del MIUR: | Area 05 - Scienze biologiche > BIO/18 - Genetica |
| Additional information: | Ciclo II/XX, Curriculum Human Genetics |
| Date Deposited: | 13 Nov 2009 13:53 |
| Last Modified: | 14 Jan 2015 12:22 |
| URI: | http://www.fedoa.unina.it/id/eprint/3325 |
| DOI: | 10.6092/UNINA/FEDOA/3325 |
Collection description
Ocular neovascularization (NV) is a feature of several common retinal and choroidal blinding diseases, including proliferative diabetic retinopathy and age-related macular degeneration. Unbalanced production of pro- vs anti-angiogenic molecules in the eye causes abnormal vessel growth. Although several pro-angiogenic pathways leading to ocular NV have been elucidated, the identification of novel molecules involved in this complex process is desirable to better understand the disease pathogenesis and to develop efficient therapeutic strategies. To this aim, we investigated the role of the morphogen Sonic Hedgehog (Shh) in the development of ocular NV. We observed that the Shh pathway is activated in the retina of the retinopathy of prematurity (ROP) and the laser-induced choroidal NV (CNV) murine models of retinal and choroidal neovascularization, respectively. We show that systemic administration of cyclopamine, a Shh pathway inhibitor, results in reduction of pathological vascularization in both models, suggesting that activation of the Shh pathway plays an important role in the ocular NV process. We then developed two nucleic acid-based systems for specific Shh inhibition in the retina: a Shh-decoy receptor (HIP--22) able to bind and sequester Shh inhibiting its pathway; and short interfering RNAs (siRNA) able to reduce 70% Shh expression levels in vitro. Both HIP--22 and the siRNA inhibited Shh-induced osteogenic differentiation of the mesenchymal cell line C3H10T1/2. In the ROP retina, adeno-associated viral vector-mediated HIP--22 delivery or periocular injections of Shh siRNA resulted in efficient inhibition of the Shh pathway but not of retinal neovascularization, even when the two strategies were combined. Stronger inhibition of the Shh pathway may be required to reduce retinal NV in the ROP model. Alternatively, the inhibition of ocular NV observed following systemic cyclopamine administration may result from secondary, extraocular effects of the Shh pathway blockade. These results suggest Shh as a potential therapeutic target for the treatment of ocular NV. Thorough characterization of Shh role in ocular NV is required for the development of an appropriate therapeutic strategy.
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