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Dissecting post-squalene cholesterol pathway and related disorders to make druggable Hedgehog-dependent tumors - CONCLUDED

Periodo
Fino al 01/04/2017
Coordinatore/trice
Prof. Gianni BALLIANO

Aree / Gruppi di ricerca

Partecipanti al progetto

Descrizione del progetto

upload_A1_dissecting.jpg

Sponsors:

University of Turin, Italy

Description

Objectives:

The study of the effect of post-squalene deficiencies and cholesterol intermediates accumulation (mainly those dependent on malfunctioning of C-4 demethylation complex) on  (i) other enzymes of post-squalene cholesterol biosynthesis, (ii) the mammalian embryo development and  (iii)  the Hedgehog protein-dependent tumors.

This study will be achieved by:

  • enzymatic assays on 3-ketosteroid-reductase deficient mouse embryos;
  • toxicity assays of 3-ketosteroids (prepared in our lab by fermentation procedure with engineered yeast strains) on Hedgehog-dependent tumor cell lines;
  • sterol profile determination and enzymatic assays on mouse embryo cell line lacking C-3 sterol dehydrogenase (C-4 decarboxylase), an enzyme belonging to the sterol C-4 demethylase complex; deficiency mimics human CHILD syndrome;
  • sterol profile determination and enzymatic assays on mouse embryo cell line lacking Erg 28p, the non-enzymatic scaffold protein of the sterol C-4 demethylase complex.

The study of the antiangiogenic and antitumoral activity of the sterol biosynthesis inhibitors and biochemical mechanism involved.

 Techniques and facilities:

  • human cell culture and in vitro enzymatic tests
  •  fully equipped laboratory for radioactive molecules and tracing of intermediate metabolites with radiolabelled precursors
  • fully equipped biochemistry laboratory for cell/tissue homogenization and protein purification
  •  protein electrophoresis and western blot
  •  fermentation laboratory for production of intermediates of cholesterol biosynthesis by recombinant yeast strains

 Collaborations:
- Matti Poutanen, Turku Center for Disease Modelling, Turku, Finland.
- Gail Herman, Herman Lab. Center for Human and Molecular Genetics, the Research Institute at Nationwide Children's Hospital, Columbus).
- Donald Poirier, Department of Molecular Medicine, Research Center and Laval University, Quebec City, Canada.
- Martin Bard, IUPU University, Indianapolis, USA

Keywords:
Cholesterol, Cholesterol biosynthesis, Inhibitors, C-4 sterol demethylase, Postsqualene sterol biosynthesis, Antitumoral activity, Antiangiogenic activity, Enzymatic activity, Cholesterol disorders, Hedgehog proteins, Cell proliferation, Signalling pathway

Links:
Turku Center for Disease Modelling

Ultimo aggiornamento: 03/07/2017 16:08
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