Progetto di Tesi Interdisciplinare in CHIMICA BIO-ORGANICA per sviluppare composti efficaci nel trattamento del GLIOBLASTOMA MULTIFORME
Studenti triennali e magistrali biotecnologie ()
giovedì 03 ottobre 2019
Nell'ambito di una collaborazione tra il Laboratorio di Translational Genomics diretto dal prof. Alessandro Quattrone (Dipartimento CIBIO) e la prof. Ines Mancini (Laboratorio di Chimica Bioorganica, Dipartimento di Fisica) si cerca uno studente/studentessa interessato/a a svolgere un progetto di tesi triennale o magistrale riguardante lo sviluppo di composti efficaci nel trattamento del glioblastoma multiforme, il più comune e aggressivo tumore cerebrale nell’adulto.
In particolare, il progetto verterà sulla sintesi organica, purificazione e caratterizzazione strutturale di analoghi di una molecola lead precedentemente identificata. L’efficacia degli analoghi verrà poi testata in vitro su cellule staminali di glioblastoma.
La persona interessata svolgerà opportune sequenze di sintesi ed imparerà l’utilizzo di metodi di purificazione (HPLC) e di caratterizzazione strutturale (Risonanza Magnetica Nucleare, Spettrometria di Massa, Spettroscopia UVVIS e Infrarosso). Avrà, inoltre, l’opportunità di testare in prima persona l’efficacia in vitro degli analoghi sintetizzati.
Inizio attività: da ottobre 2019
Three theses available preferentially for master ...
lunedì 01 aprile 2019
Three theses available preferentially for master students in 2016 at the Laboratory of Translational Genomics (http://web.unitn.it/en/cibio/11877/laboratory-translational-genomics; https://quattronelab.wordpress.com/) of the Centre for Integrative Biology of the University of Trento.
Exploiting development: epitranscriptomics for novel therapeutic strategies in neuroblastoma
Neuroblastoma is a tumor of the developing nervous system that accounts for over 50% of all pediatric cancers and poses significant challenges to developing more effective and less toxic therapy. Post-transcriptional modification of RNA might be an important mechanism driving the onset of embryonic and prenatal tumors, as its biological function has been proven to be essential during embryogenesis and development.
N6-methyladenosine (m6A) has been recently discovered as the most prevalent internal modification of mRNA. Last pieces of evidence support the notion that balanced regulation of gene expression via m6A is mainly involved in self-renewal and differentiation of stem cells. The primary goal of this project is to understand possible implications of epitranscriptomic modifications in cancer development. Precisely, we believe that altered or merely enhanced m6A methylation in tumors may guide translation of specific target mRNAs that are directly involved in regulating embryonic features. Since neuroblastoma is likely and “embryonal tumor” in which only a few somatic driving mutations that are eligible for targeted therapy have been characterized, alteration of translation during the neurodevelopmental path may represent an efficient source of clinical exploitation.
Cancer as infection: mitochondrial translation as a therapeutic target in glioblastoma multiforme
Glioblastoma multiforme (GBM) is the most advanced form (IV grade) of astrocytoma and the most common primary brain tumor in adults. Currently, the therapies available for its treatment give a very modest improvement of the average 14-month survival after diagnosis.
Recently, some solid tumors in their advanced form have been shown to depend on oxidative phosphorylation as the energy source for their development and the growth advantage. In particular, this seems to be the primary energy constraint for cancer stem cells and metastatic cells, as opposed to the well-known general dependence of bulk cancer cells on aerobic glycolysis (the so-called Warburg effect).
Oxidative phosphorylation is made possible by the protein complexes of the electron transport chain, of which 13 components only are encoded in the mitochondrial genome and translated by the mitochondrial translational apparatus. The production of these 13 proteins seems to be the limiting factor in electron transport complex stoichiometry. Mitochondrial ribosomes and polysomes are highly similar to those of bacteria, and are well know to be a toxic target of those antibacterial antibiotics - 40% of the total in use -, targeting bacterial translation.
We already completed a screening from a focused library of 180 ribosome-targeting antibacterial antibiotics in GBM cells in culture and identified by high content screening analysis some hits (compounds able to suppress mitochondrial translation and later kill cells.
TDP-43 as the “Guardian of the Transcriptome”: enhancing nonsense-mediated decay to fight Amyotrophic Lateral Sclerosis
Our aim is to validate a new drug target in ALS with TDP-43 proteinopathy, the nonsense-mediated decay (NMD) program. The reason comes from our recent discovery of a role for TDP-43 in NMD enhancement in the cytoplasm, both in vitro and in vivo (still unpublished). Together with the very recently uncovered function of TDP-43 in prevention of incorrect splicing of nonconserved cryptic exons, this feature identifies a coherent, nucleocytoplasmic role of TDP-43: preventing intronic insertion in mature mRNAs and promoting mRNA degradation by NMD when bearing these insertions. In our view, this key «guardian of the trascriptome» role of TDP-43 brings to NMD inhibition when motor neurons develop TDP-43 proteinopathy, which in turn elicits the unfolded protein response (UPR) pathway because several NMD targets are active UPR inducers. UPR progressively kills motor neurons, promoting the ALS phenotype.
With this model in the background, we will look for small molecule antagonists of the NMD-UPR axis. We will screen both upstream of the axis (compounds able to enhance NMD in TDP-43 mutant, UPR active motor neuron cells), at the axis junction (compounds able to suppress IRE1α activity), and downstream (compounds able to suppress UPR). Again in cells, we will also test for synergism of compounds belonging to two different classes.
We will finally validate the best hits in two zebrafish and a mouse mutant TDP-43 models.
Interested students are requested to email to prof. Alessandro Quattrone: email@example.com