MD/1

“Development of a synaptic magnetogenetic technology to repair brain connectivity”

prof. Lorenzo Cingolani (DSV, UniTS)

The project aims to develop an innovative approach called synaptic magnetogenetics to regulate functional connectivity of neural circuits. This technology has the potential to be used in the treatment of epilepsy, particularly in cases resistant to conventional therapies. Magnetogenetics is an emerging field of health science that merges the strengths of optogenetics and magneto-mechanical stimulations. Like optogenetics, magnetogenetics employs actuators to target specific neural circuits, while exploiting magnetic fields, rather than light, to achieve non-invasive brain stimulation. As a PhD student, you will have the opportunity to learn and apply a combination of techniques, including CRISPR/Cas9 genome editing, magnetic stimulation, electrophysiology and superresolution imaging. These techniques will be used to assess recovery of functional connectivity in mouse models of epilepsy.

Our laboratory follows an integrative experimental approach combining molecular and electrophysiological methods in both in vitro and in vivo models of neurological disorders (Thalhammer et al., 2017 Cell Rep 20, 333-343; Ferrante et al., 2021 Cell Rep 35 109248, Jaudon et al., 2022 Mol Ther Nucleic Acids 29 462-480, Moretto et al. 2023 Elife 12).

The ideal candidate is a creative and determined student. Previous experience in electrophysiology is desirable.

D/2

“Evaluation of the response to therapies in ovarian cancers”

prof. Gustavo Baldassarre (CRO, Aviano)

Role epigenetic modification in the onset of therapies resistance of ovarian cancer. Epithelial Ovarian Cancer (EOC) is a highly lethal disease, mainly for the frequent occurrence of platinum-resistant relapses (PT-Res), for which there is currently no effective therapies. PT-Res is generally associated to the resistance to PARP inhibitors (PARPi) now established as gold standard maintenance therapy for PT-sensitive EOC. Genetic alterations can explain the onset of PT-res only in a subset of EOC patients, suggesting that epigenetic regulation is involved. By this project, we will investigate the role of selected epigenetic modification in the response to PT and PARPi treatments, both impinging on alterations in the DNA damage responses. We will study, in vitro and in vivo, how selected epigenetic inhibitors could on one side improve the response to PT and/or PARPi and on the other affect the response to DNA damages. Being damaged DNA able to induce inflammatory responses, we will also study how these response are epigenetically regulated. Dissecting the molecular pathways epigenetically regulated by PT and PARPi may unveil differences between these two treatments and define novel promising therapeutic approach for patients with PT-Res disease. 

D/3

“Evaluation of tumor progression in breast cancer”

prof. Gustavo Baldassarre and Dr. Barbara Belletti (CRO, Aviano)

Approximately 70% of breast cancer (BC) express Estrogen Receptor (ER) and endocrine therapies combined with CDK4/6 inhibitors represent the mainstay for these patients. The frequent occurrence of therapeutic resistance, coupled with the unparalleled high prevalence of this malignancy, mandates new approaches to improve response and overcome resistance to these treatments. By combining transcriptomic and genetic analyses in endocrine and CDK4/6i sensitive/resistant models, we have identified novel biomarkers and putative targets against ER+ BC. Among others, expression of Amphiregulin (AREG), ligand of the ERBB family of receptors and involved in proliferation and EMT, was strongly enriched. AREG role in ER+ BC onset, progression and response to therapies will be molecularly dissected in vitro. Promising findings will be validated in preclinical models, such as patient-derived Organoids and PDX. By our better understanding of ER+ BC biology, we expect to identify tailored treatments that may in turn improve patient outcomes.

MD/4

“Personalized medicine for primary cardiomyopathies: in a model of iPSC, assessment of the role of mutations in key genes of the contractile apparatus and desmosomes in the development of dilated cardiomyopathies”

prof. Chiara Collesi (DSM, UniTS)

Molecular characterization of the functional role of mutations in key genes of the contractile apparatus and desmosomes in the development of arrhythmogenic cardiomyopathies. CMPs represent a common cause of heart failure and the most frequent cause of heart transplantation: their prevalence it's exponentially increasing. The term “arrhythmogenic cardiomyopathy” (ACM), although poorly defined, refers to a family of diseases that shares structural myocardial abnormalities with ventricular arrhythmias. It has been coined to emphasize the overlap between arrhythmogenic right ventricular cardiomyopathy (ARVC) and dilated cardiomyopathy (DCM), when heart failure (HF) caused by either could be linked to desmosomal mutations. The proposed project will focus on patients with arrhythmogenic CMP (ACMP), selected from the Heart Muscle Disease Registry of Trieste, and particularly on those carrying mutations in genes coding for key proteins in desmosomes, namely plakoglobin and desmoplakin. Desmosomes impart mechanical strength to tissues and are especially prominent in tissues subject to mechanical stress such as the skin and heart. Their importance to tissue homeostasis is emphasized by a number of cardiovascular and skin diseases associated with genetic mutation or autoimmune reactions to desmosomal components. We will assess the reliability of patient-specific cardiomyocytes (CMs), generated through the induced Pluripotent Stem Cell (iPSC) technology, 1) to reproduce their clinical data, 2) to investigate the molecular and biochemical features of the genetic defects, 3) to characterize their response to drugs using specific functional and molecular assays. The project, will therefore develop with clear dichotomous traits, both clinical and biological: one expected outcome is to validate the use of iPSC models as prognostic/diagnostic tools for a personalized therapeutic regimen, parallel to the molecular and functional characterization of mutations of genes involved in the etiopathology of ACMs. 

MD/5

“Nutritional and metabolic monitoring in real and simulated microgravity”

prof. Gianni Biolo (DSM, UniTS)

The study project will have as general objective the definition of the best nutritional approach to safeguard the astronaut's body composition (muscle and bone tissue) and the immune status during a long-term flight. The PhD student's task will be to identify and test molecular and functional biomarkers to evaluate the effectiveness of nutritional interventions in conditions of actual (astronauts during their stay on the International Space Station) and simulated microgravity (bed rest and dry immersion studies in healthy volunteers). 

MD/6

“Mechanisms of muscle catabolism and countermeasures to prevent sarcopenia”

prof. Gianni Biolo (DSM, UniTS)

MD/7

“Identification and validation of novel biomarkers related to inflammatory process and prediabetic conditions in metabolic dysfunction-associated fatty liver disease”

prof. Claudio Tiribelli (FIF, UniTS)

Metabolic dysfunction-associated fatty liver disease (MAFLD) is commonly characterized by an abnormal accumulation of fat within the liver. It is nowadays recognized as the most frequent liver disease, affecting a quarter of global population and regularly coexisting with metabolic disorders such as type 2 diabetes, hypertension, obesity and cardiovascular diseases. MAFLD can progress to more severe liver disease, including liver cirrhosis and liver cancer, which can have serious health consequences. To date, there are several gaps in the knowledge of the onset, in the factors that promotes its progression and on the pathophysiological connections between MAFLD, prediabetes and type 2 diabetes. Furthermore, there is no pharmacological treatment and the only valid approach is based on lifestyle changes, including weight loss, exercise, and a healthy diet. The present project aims to contribute to fulfill the gaps existing in this multifactorial and highly prevalent disease, combining the use of in silico approaches individuating molecular gene/protein hubs involved in MAFLD progression, in the cross-talk about the main affected organs, which could be useful as molecular targets for therapy or used in early diagnosis of the disorder. The activities of this study will be conducted in experimental models in vitro and in vivo established at Fondazione Italiana Fegato.

D/8

“Molecular events in hepatology”

prof. Claudio Tiribelli (FIF, UniTS)

Screening and validation of anti-inflammatory interventions in Parkinson's disease. Parkinson's disease (PD) is the second most common neurodegenerative condition characterized by a progressive reduction of dopaminergic neurons (DOPAn). PD prevalence is supposed to rise in the next decades paralleling the aging of the population. Diagnosis is still reached based on symptoms, mostly occurring when 40-50% of DOPAn are already lost. We recently demonstrated the determinant role of inflammation, namely TNFα, in triggering DOPAn demise in an organotypic brain culture model of the disease (OBC-SN), and the efficacy of two principles, including bilirubin, in counteracting it and preventing dopamine loss. Despite being very close to the in vivo scenario, solidly mimicking the progressive features of DOPAn demise seen in Parkinson's patients, and allowing acceding the pre-clinical stages; OBC-SN is not the best tool for drug screening. In this project, we will develop a solid in vitro slow degenerating alternative model of PD-DOPAn. Principles with a high brain bioavailability and ability to counteract inflammation, specifically TNFα, will be selected using an in silico funnel-based approach;  then screened in the developed in vitro model for efficacy in preventing (prophylactic approach) or delaying (treatment approach) DOPAn demise, and high safety profile under chronic use. Target drug transcriptomics and proteomics evaluation will be performed by biomolecular approaches. Finally, if solid principles will be identified, we will apply a translational bottom-up scheme (from in vitro to ex vivo - OBC-SN; to in vivo model) to definitively validate the principles before suggesting their use in the clinic”.

M-PNRR/9

“Identification of cellular and secreted non-coding RNAs as targets to overcome cancer therapy resistance”

prof. Licio Collavin (DSV, UniTS)

The aberrant crosstalk established between components of the tumor microenvironment (TME) and cancer cells is a critical determinant of disease progression and metastatic dissemination. In fact, therapeutic response is believed to be strongly influenced by the TME. Noncoding RNAs (ncRNA) are deeply involved in modulating the crosstalk between cancer and stromal cells, acting both in a cell-autonomous and cell non-autonomous manner, also shaping the immune environment. For this reason, they are promising targets for therapeutics and potential biomarkers.
This project aims to identify and characterize ncRNAs that can modulate tumor resistance to therapy by acting either cell-autonomously within cancer cells, or in a paracrine fashion on stromal cells. Using various tissue culture models, the project will study the impact of cancer-expressed ncRNAs in modulating the behavior of tumor cells and non-transformed cells of the TME such as fibroblasts, endothelial, and immune cells. When appropriate, the action of secreted ncRNAs on specific target genes and/or signaling pathways will be investigated to obtain relevant mechanistic insights.

M-PNRR/10

“Non-coding RNA pathways for genome instability and innate immunity in cancer”

prof. Stefan Schoeftner (DSV, UniTS)

Genomics approaches revealed that more than 85% of the human genome is pervasive to transcription. This leads to the production of classic mRNAs but also an enormous repertoire of non coding RNAs with known or potential role in cancer cell physiology. As a consequence of the vast transcriptional activity, a significant portion of the genome is present in a 3-stranded conformation, defined by an RNA:DNA hybrid and a displaced single stranded DNA loop. These atypical DNA structures are known as “R-loops”, form in cis during transcription but also in trans, and drive genome instability by provoking replication-transcription conflicts. Preliminary data from our laboratory indicate that therapy resistance cancer cells show remarkably improved R-loop resolution activity, presumably to suppress excessive risk of genome instability that results from high rates of transcription and DNA replication. We hypothesize that impairing R-loop resolution can mediate the accumulation of RNAs that mediate DNA:RNA hybrid formation and hold therapeutic relevance by triggering unsustainable DNA damage levels. The major goal of the PhD project is to identify therapeutically relevant RNA species that trigger exacerbated genome instability by forming persistent R-loops. This aim will be addressed by a combination of genomics and cell biology experiments that include the use of advanced preclinical model systems.

C/11-12

“ICGEB positions”

Housing state-of-the-art laboratories where advanced research in Life Sciences is performed makes ICGEB unique amongst Intergovernmental Organisations. ICGEB laboratories in Trieste, Italy, New Delhi, India and Cape Town, South Africa, undertake research across five macro-areas (Infectious Diseases, Non-Communicable Diseases, Medical Biotechnology, Industrial Biotechnology, and Plant Biology and Biotechnology). In Trieste, ICGEB currently runs 18 laboratories that offer a scientific environment of top international standard for both basic and applied research. Cutting edge instrumentation, specialised facilities and advanced services are available to the ICGEB investigators. The ICGEB Research Groups, comprising over 170 researchers, are active in various fields of biomedical research, including projects on cardiovascular, neurodegenerative and infectious diseases, as well as in immunology and human genetics. The success of investigations can also be measured from a series of bibliographic parameters, including the number of publications in top international scientific journals, such as Nature, Cell, Nature Medicine, Nature Reviews Cancer, Nature Reviews Molecular Cell Biology, Cell Stem Cells, Nature Structural and Molecular Biology, and Journal of Experimental Medicine, among others.

Two (2) positions are available. For more infromation, please visit the Scientific Faculty Research pages at the following link:

https://www.icgeb.org/the-faculty/

M/13

“UniTS position"

This fellowship can be linked to any of the flexible projects described at the bottom of this table (see below)

Two (2) positions are reserved for candidates from Philippines and financed by Philippine Council for Health Research and Development (PCHRD) to work at the Italian Liver Foundation in Trieste.

Translational approach for the study of the onset and progression of metabolic associated fatty liver disease (MAFLD).

MAFLD is commonly characterized by an abnormal accumulation of fat within the liver. This disorder is strongly associated with obesity and type 2 diabetes, and its increasing global incidence is worrisome. MAFLD can progress to more severe liver disease, including liver cirrhosis and liver cancer, which can have serious health consequences. To date, there are several gaps in the knowledge of the onset and the factors that promote its progression. Furthermore, there is no pharmacological treatment and the only valid approach is based on lifestyle changes, including weight loss, exercise, and a healthy diet. The present project is aimed to contribute to fulfilling the current gaps existing in this multifactorial and highly prevalent disease. The activities of this study will be conducted in experimental models in vitro and in vivo established at Fondazione Italiana Fegato.

 R/C2

Translational analysis for identification and validation of molecular targeted therapies for liver cancer

Primary liver cancer ranks as the sixth most common and the third cause of cancer-related death worldwide, where hepatocellular carcinoma (HCC) accounts for about 90% of cases.^​ Despite advances in experimental and clinical medicine, the incidence and the mortality of HCC remain high, mainly due to late diagnosis, limited therapy options, low response rate, and drug resistance. HCC is also a highly heterogeneous cancer, either within an individual (intratumoral heterogeneity) or among subjects (intertumoral heterogeneity). Previously, our group at the Fondazione Italiana Fegato ONLUS, had identified and suggested different molecular markers (e.g., oncogenes and cancer stem cells markers), both for the basic study of HCC cellular analysis and the development of future targeted therapy. These markers that might encompasses HCC heterogeneity. Still, deeper analysis on how these molecules play significant roles in various HCC cells are still needed. The aim of this project is to analyze and to asses HCC molecular targets among different HCC samples and various HCC cellular subpopulations. This project will be directed into a translational approach, by employing various biological models representing hepatocarcinogenesis and phenotypically diverse HCC cells, from in silico, in vitro, and clinical specimens, and HCC transgenic mouse model at different courses of hepatocarcinogenesis. The result of the project will be important for the development of future therapy against HCC.

F1

"Evaluation of the role of BRCA1/2 mutations in ovarian endothelial cells in neoplastic transformation"

prof. Roberta Bulla (DSV, UniTS)

F2

"Mechanisms of tumor cell mechanoprotection in immune evasion and therapy resistance"

prof. Giannino Del Sal (ICGEB and DSV, UniTS)

F3

"Co-culture systems to investigate the role of the neuromuscular junction in limb girdle muscular dystrophy"

prof. Germana Meroni (DSV, UniTS)

Mutations in the E3 ubiquitin ligase TRIM32 cause LGMD type R8, a genetic disease characterized by presence of neurological defects in addition to altered muscular physiology ultimately resulting in weakness and wasting of proximal muscles. Crosstalk between muscles and motor neurons is at the basis of neuromuscular development and maintenance, and indeed TRIM32 plays a role in regulating differentiation of both muscle and neural stem cells, suggesting that in LGMDR8 defects in these processes may be pathological. To investigate the role of TRIM32 in regulation of neuromuscular differentiation we will set up a co-culture system using two cellular models mimicking muscular and motor neurons development. TRIM32 knock out clones of either cell line will be grown together to investigate the effect of TRIM32 or its absence on the differentiation of muscle and motor neurons. Similarly, 3D culture models employing micro-fluidic devices will be established in order to generate an in vitro model of the neuromuscular synapse. The use of knock out clones will allow investigating the role of TRIM32 on the formation of the synapse and how the absence of TRIM32 on either side (muscular or neuronal) might affect neural transmission and hence maintenance of neuromuscular homeostasis. 

F4

"Novel pharmacological interventions in Rett syndrome"

prof. Enrico Tongiorgi (DSV, UniTS)

Rett syndrome (RTT) is a genetic, progressive neurodevelopmental disorder mainly caused by sporadic mutations in the X-linked methyl-CpG binding protein 2 (MECP2) gene with an incidence of 1/10.000 newborn females worldwide. Mutations leading to MECP2 ablation cause developmental arrest, loss of speech and motor abilities, seizures, breathing abnormalities and brain atrophy characterized by more closely packed neurons and decreased dendritic complexity. In previous studies, we showed that neuronal atrophy was rescued in MeCP2^y/-mice by chronic treatment with the antidepressant mirtazapine (MTZ). More recently, we identified that four FDA-approved drugs are able to rescue RTT-associated neuronal atrophy in an in vitro model of the pathology. Bioinformatic investigation of the protein pockets bound by these 4 drugs led to the identification of novel, unexpected signaling pathways that are targeted by these drugs and which may explain their positive effects in RTT. The project will involve treatment of MeCP2^y/-mice with each of the four drugs, followed by behavioral, anatomical and biochemical analysis of the drug effects. Validation of the candidate signaling pathways in vivo is included in the project.

F5

F6

F7