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SCHOOL OF MOLECULAR
BIOMEDICINE
PhD program in Molecular Biomedicine
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Fixed projects/fellowships

SIX fellowships are linked to the following projects
(listed in the order they are presented in the official call for applications)


Title and Supervisor
Description

(MD/4) The epigenetic role of the architectural chromatin factor HMGA 1 in breast cancer

Prof. Guidalberto Manfioletti,
Prof. Riccardo Sgarra
(DSV, UniTS)

HMGA1 is an architectural factor able to assemble or modulate DNA/nucleoprotein macromolecular complexes thus participating in gene expression regulation, chromatin remodelling and dynamics, replication, and DNA repair. Being a critical hub in the chromatin network, it influences a variety of biological processes such as embryogenesis and differentiation and the deregulation of its activity leads to neoplastic transformation. A deep understanding of the pathways affected by HMGA1 could therefore point-out new potential targets for cancer therapy. We explored the possibility that HMGA1 could have an influence on the epigenetic status of cancer cells and found that the level of several PTMs, linked to gene expression regulation, is regulated by HMGA1. These evidences strongly support a role of HMGA1 in regulating the cancer cell epigenome, and constitute a base for a deeper investigation regarding this aspect that we propose to exploit in two directions:
a. dissecting the mechanism by which HMGA1 contributes in modulating the epigenetic code of breast cancer cells;
b. evaluating whether "HMGA1–activated" co–activators could be specifically targeted in order to counteract breast cancer cell aggressiveness.


(MD/5) The role of RNA:DNA hybrids in genome stability

Prof. Stefan Schoeftner
(DSV, UniTS and LNCIB, Trieste)

Genomic instability is a hallmark of human cancer formation and progression. Persistent DNA:RNA-hybrids created during transcription causes the progressive displacement of the non-transcribed DNA strand, creating so called "R-loop" structures. R- loops are prone to breakage and mutagenesis, provoke replication stress, drive chromatin condensation and are highly recombinogenic. We recently identified novel factors that suppress RNA:DNA hybrid formation at transcribed telomeres thus ensuring telomere stability. Loss of function of these factors induce telomere instability, telomere length alterations, massive telomere recombination and defects in chromosome cohesion, thus suggesting an impact on cancer and aging.
The proposed PhD project will focus on the molecular mechanisms that link DNA:RNA hybrids with genomic stability and sister chromatid cohesion in human cancer.


(MD/6) Targeted therapy in cancer patient: druggable genes in colorectal cancer

Prof. Gabriele Grassi
(DSV, UniTS)

Combinatorial therapies have provided different therapeutic schedules for colorectal cancer (CRC) patients. Nonetheless, in 2016 the estimated deaths are approximately 50000 in US (American Cancer Society). Primary or acquired resistances to targeted therapies are the majors' limits to be addressed. Data from comprehensive molecular characterizations provide an opportunity to reveal new biomarkers and "druggable" genes to improve the therapeutic outcome of the patients. A shRNA screening has been done in a set of cell lines, which represent four clinically relevant CRC subtypes on 214 candidate oncogenes selected by the TCGA consortium. From this analysis, we propose new genes as therapeutic targets for CRC patients that do not respond to current therapy.

(MD/7) Role of unacylated Ghrelin in aging-associated frailty

Prof. Rocco Barazzoni
(DUCSMCS, UniTS)

The candidate will be involved in the identification of novel biomarkers predicting metabolic disease, low muscle mass and frailty in aging. Our group has recently shown that Unacylated Ghrelin (UnAG) is able to reduce skeletal muscle oxidative stress, inflammation and insulin resistance, at least in part by modulating autophagy. Since all these factors are important players in the development of aging-associated metabolic diseases, the project aims at investigating the potential therapeutic role of UnAG in this context. On one side the hypothesis will be tested that the unacylated form of the gastric hormone ghrelin (UnAG) protects from metabolic syndrome, type 2 diabetes and low muscle mass-frailty by favoring anti-inflammatory cytokines in a Friuli-Venezia Giulia aging population. On the other side the candidate will be involved in testing the impact of UnAG administration on severe inflammation and muscle catabolism in experimental disease models. Moreover, the role of autophagy will be further investigated both in vitro and ex vivo.


(D/8) Innovative therapies in myeloma: identification of new methods to functionally overcome resistant mechanism of multiple myeloma tumor cells

Dr. Gustavo Baldassarre
(CRO, Aviano PN)

Multiple Myeloma (MM) accounts more than 60.000 new cases yearly in Europe and United States, and incidence rates are increasing. Our hypothesis is that selected miRNAs delivered to MM cells can regulate the expression and function of selected targets implicated in the growth of MM cells. We propose to do so using a new immunogenomic approach based in the engineering of primary B lymphocytes for the synthesis and delivery of regulatory short non-coding RNA. Specifically, our objective is to down-regulate onco miR (miR-21) and to down regulate XBP1 hence preventing the cell ability to cope with the unfolded protein response. The three Aims are: 1) Engineer plasmid DNA coding for miRNAs targeting miR-21 and XBP1; 2) Assess whether human B cells, armed with an anti-CD38 monoclonal antibody, synthesize and deliver specific short non-coding RNAs to MM cells in an vitro model; 3) Validate the therapeutic efficacy of the new approach in a mouse model of MM.

Fellowship funded by fondazione "Ottone Zanolin ed Elena Dametto" ONLUS.
Research activity will be conducted at C.R.O. Aviano (PN).


(D/9) Understanding Ovarian Cancer dissemination and chemioresistance: Opportunities to improve patients’ survival

Dr. Gustavo Baldassarre (CRO, Aviano PN)

The project will investigate the mechanisms underlying the onset of acquired resistance to platinum and cell spreading in ovarian cancer.
The successful candidate will work in a multidisciplinary setting trying to identify through functional genomic screening and in vitro and in vivo analyses possible mediators of platinum-resistance in ovarian cancer using already available platinum-resistant cells and primary culture form recurrent ovarian cancer. He will likely use multiple assays of cellular and molecular biology to verify if Platinum-resistant cells are also able to better adhere and grown on mesothelium and which are the implicated pathways.

Fellowship funded by fondazione "Biasotto" MD OGAP ONLUS.
Research activity will be conducted at C.R.O. Aviano (PN).

 

Flexible projects/fellowships

Fellowship (M/1) and fellowships (FSE-S3/2 and 3)
can be linked to any of the following projects
(listed in alphabetical order by supervisor's name)

NOTE that FSE-S3 fellowships require submission
of a Reseaerch Project using a specific form
downloadable from the UniTS website (click HERE)



Title and Supervisor
Description

Molecular hepatology

Dr. Cristina Bellarosa
(FIF - Fondazione Italiana Fegato, Trieste)

The project is focused on the protective role of bilirubin in metabolic syndrome.
The metabolic syndrome is characterized by obesity, dyslipidemia, hyperglycemia, raised blood pressure and a proinflammatory state and it represents a multiplex risk factor for cardiovascular disease (CDV).
Bilirubin is an endogenous pigment with potent antioxidant and anti-inflammatory qualities. Gilbert's syndrome, caused by relative deficiency of glucuronyl transferase, is the commonest cause of mild congenital unconjugated hyperbilirubinemia. Several evidences from the literature demonstrate that mildly elevated serum bilirubin levels is negatively associated with the prevalence of metabolic syndrome in children, adolescents and adults and with a decrease in CDV risk.
The aim of the project is to investigate the molecular mechanisms involved in the protective role of bilirubin in metabolic syndrome. Bilirubin antioxidant and anti-inflammatory properties will be tested in in vitro models of metabolic syndrome with a particular focus on the cellular signaling activated by bilirubin. An hyperbilirubinemic animal model, the Gunn Rat, will be available to the project. Different drugs able to induce mild hyperbilirubinemia will be considered as therapeutic potential candidates.


Mechanisms of inactivation of the tumor suppressor DAB2IP in cancer

Prof. Licio Collavin
(DSV & LNCIB, Trieste
)

The RasGAP protein DAB2IP/AIP1 down-modulates the activity of multiple oncogenic pathways, such as RTK/Ras, TNF/NF-kB, VEGF, PI3K/AKT and WNT/beta-catenin, thus acting as a bona fide tumor suppressor. DAB2IP expression is frequently reduced by promoter methylation in tumors. However, in many cancers the gene is not silenced and its functions can be inactivated by other mechanisms (Bellazzo, 2016).
We discovered that DAB2IP can be disabled by interaction with mutant forms of the p53 protein, with crucial implications for tumor aggressiveness in response to inflammation (Di Minin, 2014).
The project has three aims:
1) further characterize the oncogenic impact of mutp53/DAB2IP interaction, and evaluate its diagnostic and prognostic potential;
2) identify and characterize additional mechanisms of DAB2IP inactivation in cancer, in particular by microRNAs, and evaluate their diagnostic value and potential use as targets for innovative therapy;
3) explore approaches aimed to restore DAB2IP functions in cancer cells as innovative cancer therapeutics.


Emerging pathways in ovarian cancer

Prof. Gabriele Grassi (DSV, Ospedale di Cattinara, Trieste)

The American Cancer Society estimates that in 2016 about 22,280 women will receive a new diagnosis of ovarian cancer (OC) and about 14,240 women will die from this cancer in the United States. Recent genomics data indicate that in high-grade ovarian cancer, the RB (Retinoblastoma), PI3K (phosphatidylinositol 3-kinase)/RAS, NOTCH, BRCA, FOXM1 (forkhead box M1) and TP53 signal pathways are involved. Through a multidisciplinary approach ranging from bioinformatics, molecular and cellular biology and in vivo modeling, the project aims to understand the basic mechanism of ovarian cancer development with the final go to discovery new potent drugs.

Liquid biopsy in ovarian cancer

Prof. Gabriele Grassi (DSV, Ospedale di Cattinara, Trieste)

The term "liquid biopsy" was originally coined to identify circulating tumor cells (CTCs) in the peripheral blood of oncologic patients. Today, in a broader sense, both circulating nucleic acids and extracellular vesicles are included in the term of the liquid biopsy. The advantages of liquid compared to tissue biopsies can be associated with non-invasiveness, real-time response by offering the ability to guide the choice of therapy. Unfortunately, the only FDA-approved biopsy has only a prognostic survival value. Circulating DNA and miRNA will be analyzed in a cohort of ovarian cancer patients in order to define a minimal set of prognostic markers of response to therapy. Skills in the field of bio-banking, high-through put sequencing and bioinformatics will be acquired.


Role of TRIM proteins in autophagy

Prof. Germana Meroni (DSV, Trieste)

Autophagy is a conserved degradation pathway that maintains energy homeostasis and that has been now recognized as critical for several other cellular processes. Recent data indicate that several TRIM proteins interact with and regulate pro-autophagic proteins making them excellent candidates for mediating selective forms of autophagic response.
This project aims at understanding whether a defect in the autophagy pathway is a common feature in the aetiology of human disease caused by mutations in TRIM genes. In particular, based on preliminary data implicating TRIM18 and TRIM32 in the shuttling between the primary cilium and the centrosome, the project will explore the implication of TRIM18 and TRIM32 in the crosstalk between autophagy and ciliogenesis in the regulation of morphogens and growth factors signalling. This mechanism might contribute to the pathogenesis of the human genetic diseases in which they are implicated, a malformative syndrome and a form of muscular dystrophy.


Targeting the cancer resistome to restore tumour sensitivity through novel, existing and failed drugs

Prof. Gianni Sava
(DSV, Trieste)

 

Therapy-resistant cancers harbour highly complex signalling networks - the resistome - including miRNA deregulation, inflammation, angiogenesis and tumour microenvironment. The proposed study has the ambition to investigate the resistome. To pursue this objective we propose to generate a resistance profile, or resistome, of three tumour models, two of epithelial origin, non-small cell lung cancer (NSCLC) and colorectal cancer (CRC), and the gastrointestinal stromal tumour (GIST), the most common mesenchymal tumour of the gastro-intestinal tract. The study will investigate the cross-talk between drug resistance and inflammation, drug resistance and integrin function, and the interplay of the above with stemness and angiogenesis. Ultimately, how cell-autonomous cancer phenotypes, angiogenesis and cell-extrinsic composition of the metastatic microenvironment are governed by miRNA regulatory networks will be defined.


Development of a pro-drug for the treatment of pulmonary infections in cystic fibrosis

Prof. Marco Scocchi
(DSV, Trieste)

Pharmacological treatments of cystic fibrosis (CF) patients faced with infections due to increasingly common multidrug-resistant isolates and lack of novel antibiotics. Anti-infective peptides are natural antibacterials with low incidence of resistant strains. The previously designed D-BMAP18 showed to be effective as antimicrobial against CF pathogens but also to have some cytotoxic side effects.
Aim of the project is to design, and to characterize a pro-drug that needs to be activated only in the site of infection, preventing toxic side effects and enhancing its antimicrobial potential. Different aspects including activation process, bioavailability and administration routes (e.g. micro-areosolization or nanoparticles) will also be  studied.
The candidate will operate in different research fields including applied microbiology, biochemistry, cell biology and toxicology.


Proline-rich antimicrobial peptides as new antibiotics blocking protein synthesis

Prof. Marco Scocchi
(DSV, Trieste)

 

The spreading of antibiotic-resistant pathogens is becoming an emergency. Antimicrobial peptides (AMPs) are natural molecules having strong antibiotic properties. Among them, AMPs rich in proline (PR-AMPs), other than to be active on clinically relevant pathogens, are also not cytotoxic. We recently  showed that PR- AMPs act by blocking bacterial protein synthesis.
Aim of the project is to combine all the information obtained with different PR-AMPs on the mode of action  in order to rationally improve them by basic 3D computer modelling and to design new more potent molecules for clinical applications.
The candidate will design and prepare a new generation of PR-AMPs , will study their molecular mode of action, their inhibitory activity on the protein synthesis, their in vitro and in vivo antimicrobial potential  and their toxicity and bioavailability.


Title and Supervisor
Description
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