In vivo determinants for neuronal bilirubin toxicity, biomarkers detection and pre-clinical trials in the Gunn rat.

Project Description:

The Fondazione Italiana Fegato has a long research background on the molecular mechanisms involved in bilirubin toxicity/resistance to the central nervous system in relation to Crigler-Najjar Type I syndrome and Kernicterus (see publications on this site). In this rare, neurological, sub lethal (nevertheless seriously disabling) pathology, the availability of in vivo research model mimicking the human condition is essential to overcoming the lack of samples. They are even more un-substitutable when a new treatment has to be tested (preclinical trial). We will take advantage of the Gunn rat, the unique natural model (spontaneous mutation in a Wistar colony in the 1936) for Crigler-Najjar Type I syndrome, that parallel several features of the human condition, for completing and confirming results obtained by the use of in vitro models (cell lines, primary cell cultures, BOC). We are studying the molecular events leading to toxicity vs. resistance in different brain regions (cortex, cerebellum, striatum, hippocampus, superior and inferior collicula) at different post-natal ages. We are also using this suitable model for the individuation of biomarkers of brain damage and, most importantly, for the pre-clinical evaluation of new therapeutical approaches for reducing (or desirably avoid) the handicap linked to this pathological condition.

 

Scientists involved:

Silvia Gazzin, PhD-Senior Researcher (Scientific Coordinator)

Eleonora Vianello, PhD Student 2014-2016

Faina Aptisionak, under graduated student (during 2012)

Giulia Furlan, under graduated student (during 2011)

Celeste Maria Robert, PhD Student 2009-2011

Andrea Berengeno, PhD Student 2008-2010

Claudio Tiribelli, MD, PhD- FIF Scientific Director

Period: 2008-2016

Funding Source:

Fondazione Italiana Fegato in house grant

PhD Fellowship ( 2014-2016) of Eleonora Vianello was in part supported by Università degli Studi di Trieste, Scuola di dottorato in Biomedicina Molecolare

PhD Fellowship ( 2008-2010) of Andrea Berengeno and Celeste Maria Robert  was supported by Ministero Affari Esteri (MAE)

 

Publications:

Alterations in the cell cycle in the cerebellum of hyperbilirubinemic Gunn rat: A possible link with apoptosis? - María Celeste Robert, Giulia Furlan, Natalia Rosso, Sabrina Eliana Gambaro, Faina Apitsionak, Eleonora Vianello; Claudio Tiribelli, and Silvia Gazzin. PLosOne, November 2013, Volume 8, Issue 11 - e79073

Bilirubin accumulation and Cyp mRNA expression in selected brain regions of jaundiced Gunn rat pups. Gazzin S, Zelenka J, Zdrahalova L, Konickova R, Zabetta CC, Giraudi PJ, Berengeno AL, Raseni A, Robert MC, Vitek L, Tiribelli C.Pediatr Res. 2012 Jun;71(6):653-60.

Modulation of Mrp1 (ABCc1) and Pgp (ABCb1) by bilirubin at the blood-CSF and blood-brain barriers in the Gunn rat. Gazzin S, Berengeno AL, Strazielle N, Fazzari F, Raseni A, Ostrow JD, Wennberg R, Ghersi-Egea JF, Tiribelli C. PLoS One. 2011 Jan 31;6(1):e16165.

Poster and Oral Presentations:

LV Reunión Annual de la Sociedad Argentina de Investigación Clínica (SAIC), November 2010. Berengeno Andrea, Gazzin Silvia, Bellarosa Cristina, Robert M. Celeste, Tiribelli Claudio. “Impact of bilirubin on the ABCC1 expression in brain parenchyma in vivo” (Poster Presentation).

3rd Congress of the European Academy of Paediatric Societies (EAPS), October 2010. Berengeno Andrea, Gazzin Silvia, Bellarosa Cristina, Robert M. Celeste, Tiribelli Claudio. “Does Bilirubin affect the ABCc (Mrp1) expression in the brain of the Gunn rat?” (Poster Presentation).

Federation of European Laboratory Animal Science Associations (FELASA), June 2010. P. Zarattini, M. Stebel, S. Gazzin, A. Berengeno, J. Zelenka, L. Zdrahalova, R. Konickova, L. Vitek and C. Tiribelli. “XXI century improvement of a historical animal model for Crigler Najjar type I syndrome: rederivation of the normobilirubinemic jj genotype as a true control for the Gunn jaundiced rat” (Poster Presentation).

Pedriatric Academic Societies (PAS), May 2010. Berengeno Andrea, Gazzin Silvia, Zelenka Jaroslav, Zdrahalova Lucie, Robert M. Celeste, Raseni Alan, Vitek Libor, Tiribelli Claudio. “Bilirubin and the ABCc1 expression in the brain of the Gunn rat” (Poster Presentation).

FEBS-ABC meeting, February 2010. Berengeno Andrea, Gazzin Silvia, Bellarosa Cristina, Robert M. Celeste, Tiribelli Claudio. “Effect of bilirubin on ABCC1 expression in brain selective regions of Gunn rats” (Poster Presentation).

FEBS-ABC meeting February 2010. Silvia Gazzin, Francesco Fazzari, Alan Raseni, Andrea Berengeno, Jean-Francois Ghersi-Egea, Claudio Tiribelli. “May unconjugated bilirubin affect the expression of ATP Binding Cassette (ABC) transporters (Pgp and  Mrp1) at the blood brain barriers” (Poster Presentation).

Trieste Yellow Retreat (TYR, March 2010). Berengeno Andrea, Gazzin Silvia, Tiribelli Claudio “Does Bilirubin affect the Mrp1 expression in the Central Nervous System of the Gunn rat?”.(Oral Presentation)

6th Annual North American ABC Meeting, September 2009. Berengeno Andrea, Gazzin Silvia, Zelenka Jaroslav, Zdrahalova Lucie, Robert M. Celeste, Raseni Alan, Vitek Libor, Tiribelli Claudio. “Impact of Bilirubin on the ABCc1 expression on brain parenchyma  in Gunn rats”(Oral Presentation).

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