Browsing by Author "D’Antona, Lucia"

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    Inhibition of serum- and glucocorticoid-induced kinase 1 ameliorates hydrocephalus in preclinical models
    (BMC, 2023-08-18) Hochstetler, Alexandra; Smith, Hillary; Reed, Makenna; Hulme, Louise; Territo, Paul; Bedwell, Amanda; Persohn, Scott; Perrotti, Nicola; D’Antona, Lucia; Musumeci, Francesca; Schenone, Silvia; Blazer‑Yost, Bonnie L.; Biology, School of Science
    Background: Hydrocephalus is a pathological accumulation of cerebrospinal fluid (CSF), leading to ventriculomegaly. Hydrocephalus may be primary or secondary to traumatic brain injury, infection, or intracranial hemorrhage. Regardless of cause, current treatment involves surgery to drain the excess CSF. Importantly, there are no long-term, effective pharmaceutical treatments and this represents a clinically unmet need. Many forms of hydrocephalus involve dysregulation in water and electrolyte homeostasis, making this an attractive, druggable target. Methods: In vitro, a combination of electrophysiological and fluid flux assays was used to elucidate secretory transepithelial electrolyte and fluid flux in a human cell culture model of the choroid plexus epithelium and to determine the involvement of serum-, glucocorticoid-induced kinase 1 (SGK1). In vivo, MRI studies were performed in a genetic rat model of hydrocephalus to determine effects of inhibition of SGK1 with a novel inhibitor, SI113. Results: In the cultured cell line, SI113 reduced secretory transepithelial electrolyte and fluid flux. In vivo, SI113 blocks the development of hydrocephalus with no effect on ventricular size of wild-type animals and no overt toxic effects. Mechanistically, the development of hydrocephalus in the rat model involves an increase in activated, phosphorylated SGK1 with no change in the total amount of SGK1. SI113 inhibits phosphorylation with no changes in total SGK1 levels in the choroid plexus epithelium. Conclusion: These data provide a strong preclinical basis for the use of SGK1 inhibitors in the treatment of hydrocephalus.
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    Kinase Inhibitors in Genetic Diseases
    (MDPI, 2023-03-09) D’Antona, Lucia; Amato, Rosario; Brescia, Carolina; Rocca, Valentina; Colao, Emma; Iuliano, Rodolfo; Blazer-Yost, Bonnie L.; Perrotti, Nicola; Biology, School of Science
    Over the years, several studies have shown that kinase-regulated signaling pathways are involved in the development of rare genetic diseases. The study of the mechanisms underlying the onset of these diseases has opened a possible way for the development of targeted therapies using particular kinase inhibitors. Some of these are currently used to treat other diseases, such as cancer. This review aims to describe the possibilities of using kinase inhibitors in genetic pathologies such as tuberous sclerosis, RASopathies, and ciliopathies, describing the various pathways involved and the possible targets already identified or currently under study.