Inhibition of the Sonic Hedgehog pathway as a strategy to treat ocular neovascularization in animal models

Cotugno, Gabriella Inhibition of the Sonic Hedgehog pathway as a strategy to treat ocular neovascularization in animal models. [Tesi di dottorato] (Inedito)

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Abstract

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.

Tipologia di documento:Tesi di dottorato
Parole chiave:Ocular Neovascularization, Diabetes, Gene Transfer
Settori scientifico-disciplinari MIUR:Area 05 Scienze biologiche > BIO/18 GENETICA
Coordinatori della Scuola di dottorato:
Coordinatore del Corso di dottoratoe-mail (se nota)
Salvatore, Francescosalvator@unina.it
Tutor della Scuola di dottorato:
Tutor del Corso di dottoratoe-mail (se nota)
Auricchio, Albertoauricchio@tigem.it
Pastore, Luciopastore@ceinge.unina.it
Ali, Robinr.ali@ucl.ac.uk
Stato del full text:Accessibile
Numero di pagine:153
Istituzione:Università degli Studi di Napoli Federico II
Dipartimento o Struttura:Telethon Institute of Genetic and Medicine (TIGEM)
Tipo di tesi:Dottorato
Stato dell'Eprint:Inedito
Scuola di dottorato:Scuola Europea di Medicina Molecolare - SEMM sede di Napoli
Denominazione del dottorato:PhD in Molecular Medicine, curriculum Human Genetics
Ciclo di dottorato:XX
Numero di sistema:3325
Depositato il:13 Novembre 2009 14:53
Ultima modifica:13 Novembre 2009 14:53

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