• Responsabile Scientifico: Francesco Brun
• Dipartimento: DIA
• Codice Progetto: P2022R2YW3_003
• CUP: J53D23018060001
• Contributo MUR: € 69.324 

Abstract: Multiple sclerosis (MS) is one of the most common causes of neurological disability in young adults in the Western world, affecting more than 2 million people worldwide. In this disorder, the patient's immune system attacks the myelin sheath or the axons, causing inflammation and leading to irreversible neurological disability. Unfortunately, there are currently no widely used regenerative therapies in MS. In this context, the introduction of a non-invasive treatment promoting remyelination in MS patients has the potential to reduce long-term disability. Recent neuromodulation (i.e., targeted neuronal stimulation or inhibition) studies have focused on the possibility of mitigating symptoms as well as of improving neurorehabilitation in MS patients through cortical/deep electrical (ES) and transcranial magnetic (TMS) brain stimulation techniques. However, these techniques show several drawbacks due to shallow reach within the brain (TMS and cortical ES) or to extreme invasivity in the case of deep ES actuated through electrode implantation. Transcranial low-intensity focused ultrasound (FUS) neurostimulation is an extremely promising technique currently in use in several clinical trials. Compared to other noninvasive techniques, FUS a) affords much better focusing (1 mm) and b) seamlessly reaches deep brain structures otherwise only accessible through electrode implantation. FUS is therefore poised to become the instrument of choice to focally promote remyelination. In addition, no gold standard technique for measuring myelin in vivo with good sensitivity and specificity is currently available. myREPAIR has the ambitious goal of introducing both a new treatment of demyelinated lesions in MS but also a new imaging method that can quantify the degree of demyelination in this disease. In-vitro experiments will be performed to investigate the biological mechanisms underlying remyelination processes activated by different FUS protocols. The stimulation protocol with highest myelin repair potential will be employed in an in vivo study on an autoimmune MS mouse model. Myelin will be quantified in vivo through a novel, FDA approved, MRI-based myelin quantification technique (REMyDI: Rapid Estimation of Myelin for Diagnostic Imaging). Crucially, we will employ ex vivo X Ray Phase-Contrast micro/nano Tomography (XPCT) and micro-X-ray diffraction (SmXRD) with synchrotron radiation beams, hence associating 3D nano-scale axon morphology (XPCT) with quantitative assessment of myelin concentration (SmXRD). These techniques will help to shed light on the biological mechanisms of MS and of the interaction of acoustic stimuli with neuronal cell membranes. Overall, this project will lay the groundwork for clinical translation of a noninvasive remyelination treatment for MS through FUS as well as for new treatments inducing myelin repairs in several demyelinating diseases.
 

• Responsabile Scientifico: Fabio Candotto
• Dipartimento: Scienze della Vita
• Codice Progetto: P2022Y37WC_001
• CUP: J53D23018610001
• Contributo MUR: € 93.000 

Abstract: The main aim of the project "Nano 2-Bees: exposure and toxicity of 2D-nanomaterials in the plant-pollinator system" is to improve the knowledge on the exposure routes through which 2D-nanomaterials (2DNMs) involuntary released into the environment could reach the main actors of the sexual reproduction of entomophilous plants, i.e. flowers and pollinators, and to verify possible toxic effects on both. In fact, 2DNMs are becoming widely used for state-of-the-art technological applications but also in construction materials, such as asphalts and concretes, that are already available in the market and that will become commonplace in our everyday life. Therefore, a future release into the environment of 2DNMs is foreseen and it is raising concerns at both scientific and EU regulatory level. Recently, it was showed that environmentally relevant aerial depositions of a commercial graphene oxide, one of the most used 2DNMs, on the stigmatic surfaces of an entomophilous plant could impair the normal development of seeds, affecting de facto the sexual reproduction process. For this reason, Nano 2-Bees will extend the investigations on 2DNMs exposure routes, as well as on their toxicity, to several entomophilous plants and to their most important pollinators, i.e. bees and bumblebees, for which there is an almost complete lack of data.
The project will be conducted by three research units (RUs), namely the University of Trieste (UniTs), that will be the coordinator, University of Torino (UniTo) and University of Bologna (UniBo), each of them carrying out one or more work packages of the project, alone or in strict collaboration with the other RUs. 
UniBo will investigate the exposure route involving the translocation of 2DNMs through the plant, from roots to leaves and to the nectars, as possible final destination (with UniTs), with microscopy techiques. In addition, UniBo will assess possible effects of 2DNMs on the development of plants, from seedling to adults, and the flowering process, monitoring the development of reproductive structures (i.e. the androecium and the gynoecium) and the viability of pollens. 
UniTs will explore the exposure route involving aerial and pollinator-conveyed (with UniTO) depositions of 2DNMs into the corolla of flowers, with particular attention to depositions interesting the stigma and the nectars. These analysis will be conducted with Microscopy techniques, such as SEM and Confocal microscopy. UniTs will also investigate the effects of 2DNMs depositions on the stigmas, pollen-stigma interactions and on the development of seeds using in-house developed protocols. UniTs will also take part on the detection of 2DNMs in the nectar aided by a research team of chemists of the University of Castilla La Mancha (Ciudad Real, Spain) which has a long standing collaboration with UniTs on the study of graphene related materials.
UniTo will explore the 2DNMs exposure routes involving pollinators, by investigating the collection, accumulation on the body, and the transport of 2DNMs from contaminated surfaces (including flowers), to flowers (with UniTs) and to the hive. UniTo will apply standard protocols on bees and bumblebees to assess the lethal and sub-lethal doses of 2DNMs (incl. behavioural effects) from acute and chronic exposures by contact and ingestion. UniTo will also test possible interaction effects derived from the simultaneous presence in the environment of 2DNMs and commonly used pesticides.
All the activities will be conducted using the same 2DNMs, i.e. graphene oxide and molybdenum disulphide, and several species of entomophilous plants and pollinators selected for their suitability for some or all the experiments that will be conducted, as appropriate.
In summary, this proposal foresees interdisciplinary research activities as scientists with different backgrounds, i.e. botanists, entomologists and chemists, put together their respective expertise to deal with several environmental issues related to the advent of present and future technological advancements. The topic faced fits the PNRR strategic emerging topic "Sustainability and Protection of Natural Resources", cluster 6 "Food, Bioeconomy, Natural Resources, Agriculture and Environment" as it involves performing basic and applied research aimed at preventing biodiversity decline and preserving ecosystems through the acquisition of improved knowledge and innovation. In fact, the Nano 2-Bees project will provide fundamental data for the prediction of (i) one of the possible fates of 2DNMs on lands and (ii) the possible impacts of 2DNMs on a biological process that contributes to sustain the biodiversity of entire ecosystems as well as a large part of food production for humankind.
 

• Responsabile Scientifico: Fabrizia Cesca
• Dipartimento: Scienze della Vita
• Codice Progetto: P2022EZ9LN_002
• CUP: J53D23016090001
• Finanziamento MUR: € 119.686

Abstract: Epilepsy is a neurological disorder characterized by repeated seizures. Different therapeutic approaches are available but, unfortunately, about 30% of patients do not respond to medical therapies. Over the past decade, optogenetics has emerged as a tool for exploring the dynamics of neuronal networks and treating neurological conditions such as epilepsy. The optogenetic strategy is based on the expression, in precise areas of the brain, of light-sensitive proteins called opsins that are capable of modifying the membrane potential according to the specific wavelength illumination, usually obtained using computer-based hardware. Despite the numerous advantages of this technique, research still faces practical and translational challenges due to the difficulties of illuminating multiple and deep areas of the brain. In this scenario, the search for alternative light sources is a goal to be achieved. Luciferases are enzymes capable of emitting light upon addition of their substrate coelenterazine and can be used to provide light to opsins and modulate their action.
In this project, we aim to develop a closed-loop sensor called pHIL (pH-sensitive inhibitory luminopsin) with the aim of inhibiting the generation of seizures. pHIL is composed of a bioluminescent protein, RLuc8, coupled to the inhibitory opsin eNpHR3.0. In the proposed strategy, seizure control will occur only under the acidic intracellular conditions observed in epileptic neurons. The pH sensitivity of the probe is provided by a pH sensor, a pH sensitive variant of EGFP, called E2GFP. The functioning of the probe is based on the BRET mechanism: the UV light produced by the luciferase is transferred to E2GFP, which in acidic conditions will emit light and activate eNpHR3.0, favoring the hyperpolarization of the epileptic neuron membrane. Our preliminary data show that the pHIL sensor is expressed and localized to the plasma membrane in HEK293T cells and primary hippocampal neurons. Furthermore, pHIL hyperpolarizes HEK293T cells under conditions of extracellular acidity and upon addition of CTZ 400a, the specific substrate of luciferase capable of inducing the emission of UV light. Based on our data, therefore, we propose pHIL as a potential therapeutic tool to counteract neuronal hyperexcitability.
 

• Responsabile Scientifico: Giannino Del Sal
• Dipartimento: Scienze della Vita
• Codice Progetto: P2022ZWY8H_002
• CUP: J53D23019200001
• Finanziamento MUR: € 61.469 

Abstract: Post-translational modifications (PTMs) of proteins are critical for appropriate cellular responses to intra- and extra-cellular stimuli. A crucial PTM in signal transduction is provided by phosphorylation-dependent cis-trans prolyl isomerization of phosphorylated Ser/Thr-Pro motifs, which results in conformational changes affecting the structure of specific domains with impact on protein function. In humans, the only known enzyme that specifically isomerizes phospho-Ser/Thr-Pro motifs is the peptidyl-prolyl isomerase Pin1. High Pin1 levels are prevalent in tumors,1 and we and others found that it modulates multiple signaling pathways relevant for cancer growth, metastasis, and treatment resistance.2 Abnormal Pin1 activation simultaneously boosts multiple oncogenes, while depletion or pharmacological inhibition of Pin1 in experimental mouse models curbs tumor growth and metastasis, making Pin1 an ideal drug target.3 Thus, considerable effort for developing Pin1 target therapies has been made, yet the provided inhibitors mainly display low potency, specificity, stability, and permeability.2, 4 A research program dedicated to designing Pin1 inhibitors is active in our consortium since 2015. Such program already identified KPT-6566, a potent Pin1 inhibitor able to force its degradation. Acting as covalent inhibitor, it exhibits significant antitumor activity in nude mice (5 mg/kg, ip injection). 5 In recent years, our drug development program identified other new hits able to inhibit Pin1 with the same potency of all-trans retinoic acid (ATRA), one of the most studied Pin1 specific inhibitor. 6 The hits could be clustered into two groups: ATRA analogs and pyrazole chemotypes derived from UniTO library screening. This proposal is dedicated to identifiy new Pin1 inhibitors, characterized up to preclinical level. We will pursue a lead optimization campaign, by using a structure-based computationally driven approach, starting from the above-described hits (see preliminary results). We will apply an iterative optimization cycle, supporting the drug optimization process by structural studies and state of the art in silico analysis. The best candidates will be then evaluated for in vitro metabolic profile and stability in biological fluids. Antitumor activity of the best compounds will be investigated in 2D and 3D models of breast cancer (2D cultures, tumor-derived spheroids and mouse- and patient-derived organoids). Once the lead molecule(s) will be identified, toxicity and pharmacokinetic profile in mice will be endorsed. Analysis will be performed exploiting advanced miniaturized biosampling and sample treatment technologies coupled to original mass spectrometry-based methods 7 in order to reduce sample volumes, solvents and reagents, in the general framework of sustainability.
 

• Responsabile Scientifico: Marco Gerdol
• Dipartimento: Scienze Mediche, Chirurgiche e della Salute
• Codice Progetto: P2022JEEMT_002
• CUP: J53D23013780001
• Contributo MUR: € 98.000
 

Abstract: Mussels are important components of the benthic community, acting as bioengineers as well as important aquaculture species. The National production of the Mediterranean mussel Mytilus galloprovincialis exceeds 64,000 tonnes/year. Mussel display a remarkable phenotypic plasticity, a high tolerance to biotic and abiotic stressors, and a continuously expanding range of distribution. As filter-feeders, they are constantly exposed to a wide range of potentially pathogenic microorganisms, including bacteria, protozoans and viruses. Nevertheless, compared to other commercially important bivalve species, mussels are less impacted by massive mortality events which characterise the aquaculture sector worldwide. Due to their tolerance to biotic toxins and pollutants, mussels can accumulate these compounds causing relevant health concerns for human consumption and economic losses for the productive sector.
Even though the bases of these peculiar traits are not entirely clear, a combination between genetic and environmental factors likely contribute to enhancing mussel resilience and adaptation potential. The recent release of the M. galloprovincialis genome has revealed on unexpectedly high level of hemizygosity, with extended presence-absence gene variations among individuals. This is consistent with the presence of an open pangenome, which so far has been almost exclusively reported in prokaryotes, with limited evidence also in plants and fungi. The mussel pangenome has been so far investigated in a small number of individuals belonging to two populations only, which cannot be considered as representative of the broad genomic diversity of this species. Far to be exhaustive, this analysis has revealed that 25% of the mussel genes are dispensable, i.e. potentially absent in individual genomes, and mostly belong to expanded gene families potentially involved in immune responses and survival. The association between PAV and hemizygosity strongly suggests the existence of significant diversity between the two genomic haplotypes, which could be certainly extended at the population and species levels.  
These unique genomic features have been possibly linked to the local adaptation, explaining the extraordinary resilience to stress displayed by mussels, which may underpin the presence of population-specific gene-encode molecules conferring these traits. 
The HAMIGA project aims to provide a comprehensive overview of the M. galloprovincialis haplotype diversity, by targeting three representative genomes of mussels belonging to geographically separated populations and extending the analysis to a statistically significant number of individuals from each population. Fully phased individual genomes will be obtained through a combination of long reads (PacBio HiFi) and the construction of chromosome conformation capture libraries (HiC) and will be organised in a pangenome graph. Based on the identification of the core genomic regions shared by these references, HAMIGA will develop an approach based on Nanopore adaptive sequencing in order to selectively target dispensable genomic regions from additional individuals, allowing the construction of a comprehensive collection of dispensable pangenomic regions. Population-specific genes will be linked to local biological features, potentially allowing the identification of adaptive traits.
 

• Responsabile Scientifico: Guidalberto Manfioletti
• Dipartimento: Scienze della Vita
• Codice Progetto: P202288PXS_001
• CUP: J53D23017400001
• Finanziamento MUR: € 80.373
 

Abstract: Triple-negative breast cancer (TNBC) is a heterogeneous subtype of tumor. Patients with TNBC have a relatively poorer outcome compared to those affected by other BC subtypes, because of the typically aggressive cancer behavior and the absence of recognized targets for specific therapies. In the last decade considerable efforts have been made to better understand the biological characteristics of TNBC trying to define different subtypes in order to help clinicians in providing better prognosis and in proposing therapeutic approaches based on molecular peculiarities.
In this project we will exploit the architectural transcription factor HMGA1, a master regulator in TNBC-related key processes, able to modulate chromatin structure and function, reprogramming the gene expression program in cancer cells leading to EMT and stemness, cell migration and invasion, anchorage independent growth, metastasis formation in vivo, and chemoresistance. We will integrate bioinformatics analyses on TNBC gene expression dataset with RNA-Seq data obtained from TNBC cellular models silenced for the expression of HMGA1 in order to find out relevant factors and pathways involved in TNBC onset and progression that will be validated in cellular models and in patients to be used as biomarkers and/or prognostic factors.  The same cellular models will be exploited to characterized the HMGA1-dependent miRNA content of cancer cell-derived extracelluar vescicles (EVs) that will be evaluated in blood patients samples as a possible biomarker and prognostic factor.
This project is aimed at clarifying new pathways and extracellular factors involved in TNBC  by exploiting the alterations induced by the modulation of the expression of HMGA1, a critical factor in BC. The final goal is to discover biomarkers, prognostic factors, and molecular targets to fill the gap of the yet partially unfulfilled clinical demands.
 

• Responsabile Scientifico: Alessio Mortelliti
• Dipartimento:  Scienze della Vita
• Codice Progetto: P2022K42XX_001
• CUP: J53D23013810001
• Finanziamento MUR: € 157.577 
 

Abstract: Up to 50-90% of plants depend on animals for seed dispersal. As an example, in temperate ecosystems, oaks (Quercus spp.) and beech (Fagus spp.) depend largely on small mammals such as mice and squirrels for the dispersal of their seeds. This relationship between seeds and small mammals has been forged over millions of years of coevolution, however, as plant ranges rapidly shift due to climate change or as alien plant species arrive in new areas, the first dispersing seeds might be faced with individuals that may have not previously encountered that particular seed. We call these seeds ‘novel’, as opposed to ‘familiar’ seeds that are currently present within the range of seed dispersers. Since recent work has shown that the personality of small mammals, such as the level of boldness and curiosity of an individual, affects all the stages of seed dispersal, we ask whether some individuals, such as bolder or more curious individuals, are more likely to disperse novel seeds. To date this question remains unanswered yet the consequences for the functioning of ecosystems are critical, as the implications are that some individuals may be of disproportionate importance for allowing plants to adapt to climate change and for affecting the spread of invasive species. If our hypothesis that some individuals are more likely to disperse novel seeds is confirmed, this would require a paradigm-change in the way we manage for climate change and invasive species. Specifically, it would require the need to foster the survival of these disproportionally consequential individuals. 
To contribute in filling this knowledge gap we plan to conduct a large-scale field project in the northeast of Italy focusing on individual personality and seed dispersal. Specifically, we will conduct two field experiments wherein we will measure personality in wild living rodents and expose them to novel and familiar seeds. By tracking each seed and measuring their germination rates, we will be able to associate each individual small mammal to the fate of the dispersed seeds. We capitalize on more than 7 years of field research conducted by one of the PIs on this topic, with all the field methods extensively tested in a variety of conditions. In addition to evaluating whether certain personality traits increase the likelihood of seed dispersal, we will also identify seed traits that increase the chances of a seed being predated or dispersed. Finally, by conducting a series of computer simulations with agent based models parameterized with the results of our field experiments, we will assess the potential effects of behavioral phenotypes on forest community composition.
We will contribute to the advancement of science by testing, for the first time, a key hypothesis on the importance of individual variation in behavior for the dispersal of seeds in response to global change. Likewise, the project will also have important applied consequences: as an example we will produce a free booklet focused on how to capitalize on the role of rodents to improve the practice of assisted migration. We will also develop a checklist of plant traits and species that will allow managers to identify likely ‘winners’ and ‘losers’ in terms of the potential for successful expansion.
 

• Responsabile Scientifico: Katia Rupel
• Dipartimento: Scienze Mediche, Chirurgiche e della Salute
• Codice Progetto: P2022NC9NT_002
• CUP: J53D23014280001
• Finanziamento MUR: € 60.804

Abstract: The aim of the project is to develop and characterize a new biomaterial for bone regeneration, reaching a pre-clinical experimentation level. The study will be articulated over two years in three main working blocks (WB). During WB1, the synthesis and chemical/physical characterization of a biomaterial based on fibroin/BCTP will be performed. During WB2, the scaffold will be evaluated with respect to the in vitro cellular response. Finally, in WB 3 the ability to promote bone regeneration in an animal model will be evaluated.
The results that the research group expects from this study are mainly linked to the osteoinductivity and osteoconductivity properties of the new biomaterial, which should be enhanced by the presence of a scaffold capable of: stimulating and supporting the colonization by cells of the surrounding tissues , maintain the mechanical properties necessary for bone regeneration for the entire duration of the experiment and be degraded by the microenvironment while simultaneously releasing pro-osteogenic stimuli.
 

• Responsabile Scientifico: Stefan Schoeftner
• Dipartimento: Scienze della Vita
• Codice Progetto: P2022RSP2C_002
• CUP: J53D23017520001
• Finanziamento MUR: € 102.925 
 

Abstract: R-loops are persistent three-stranded nucleic acid structures composed of a DNA: RNA hybrid, a displaced single-stranded (ss)DNA, and a trailing ssRNA overhang. R-loops cover up to 5% of the human genome and act as physiological intermediates in a variety of biological processes. R-loops are enriched in highly transcribed regions, C/G rich sequences and repetitive elements such as telomeres, centromeres and ribosomal genes. Multiple pathways comprising RNaseH enzymes, topoisomerases, histone chaperons and helicases prevent unprogrammed R-loop formation. Conversely, impaired R-loop resolution causes transcription-replication collisions (TRC), or stalled replication forks that lead to replication stress and genomic instability. A series of oncogenes including H-RASV12 drive R-loop accumulation and genomic instability, in contrast, major tumor suppressors limit R-loop formation, to safeguard genomic stability. Vertebrate telomeres represent a hallmark model to investigate R-loop management in a cancer relevant setting. Transcription of telomere tandem repeats gives rise to UUAGGG telomere repeat containing, long non-coding RNAs (TERRA), that are prone to form R-loops at telomeres and at interstitial telomeric sequences (ITSs). Here, we will investigate whether un-programmed R-loops at telomeres and other repeats trigger paraspeckle aggregation to ensure efficient R-loop resolution, genomic stability and escape from cGAS/STING mediated activation of innate immunity. Understanding the biology of R-loop management and related genomic instability pathways in cancer cells using telomeres as model system, will provide new inroads in developing innovative approaches that aim to exacerbate genomic instability in cancer cells and improves anti-cancer immune responses.
 

• Responsabile Scientifico: Giovanni Sorrentino
• Dipartimento: Scienze Mediche, Chirurgiche e della Salute
• Codice Progetto: P2022A9J9L_002
• CUP: J53D23014210001
• Finanziamento MUR: € 112.195 
 

Abstract: Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease with a prevalence of 25% in the western world. It represents a continuum of liver abnormalities spanning from nonalcoholic fatty liver (NAFL) to nonalcoholic steatohepatitis (NASH), observed in about 30% of NAFLD patients. NASH can further develop in cirrhosis, and finally, liver cancer. Mechanistically, the build-up of hepatic fat is a necessary step for NAFL initiation and its uncontrolled persistence fuels disease progression. Unfortunately, there is no approved drug in the market for the treatment of this devastating disease.
The PIDDosome is a multiprotein complex composed of three members and its assembly results in the activation of the endopeptidase Caspase-2. In recent years, solid work exploiting animal models and patient samples has demonstrated that PIDDosome subunits become aberrantly activated in NAFLD and that they are crucial to support NASH progression. Thus, PIDDosome inhibition, as well as elements controlling its unscheduled expression in the liver, have been proposed as promising therapeutic targets to contrast NAFLD progression to NASH. However, the mechanisms underlying PIDDosome activation in NASH remain a medical enigma.
In this project, we will apply a multidisciplinary approach to unravel the intricate molecular events leading to PIDDosome activation during NAFLD evolution, using state-of-the-art genetic tools, as well as human iPSC-derived organotypic cultures and diet-induced mouse models of the disease.
To this aim, our grant proposal brings together the diverse expertise of two emerging young scientists with a long-standing interest in modelling metabolic diseases exploiting organoid technologies and in PIDDosome regulation, respectively.
Our endeavor builds on a unique and unprecedented set of preliminary data revealing that PIDDosome functionality critically depends on the METTL3 methyltransferase and its adaptors (dubbed as m6A writer). Of note, the m6A writer, crucial for the methylation of the N6 position of adenosine (m6A) in selected mRNAs, is an emerging regulator of gene expression at mRNA level and it has been proved to be druggable in preclinical settings. Thus, with our proposal we will unveil mechanistic aspects of a signaling pathway, contextualized into a common disease representing a major socioeconomic burden of our society, that has the potential to uncover unexpected routes for therapeutic intervention.
We believe this project explores a medically relevant new concept, is based on solid preliminary results, and proposes cutting edge methodologies, while remaining feasible in light of past scientific contributions of the PIs and their peculiar expertise.
 

• Responsabile Scientifico: Serena Zacchigna
• Dipartimento: Scienze Mediche, Chirurgiche e della Salute
• Codice Progetto: 
• CUP: J53D23019150001
• Finanziamento MUR: € 112.509 

Abstract: Comparing to normal tissues, tumor vessels are aberrant at the phenotypic and functional levels, compromising the efficacy and the safety of current anti-angiogenic strategies. Thus, a better understanding of tumor vasculature molecular features is essential to develop effective cancer vessel-specific anti-angiogenic approaches.
Alternative Splicing (AS) has a major role to expand the coding potential of the human genome. Notably, aberrant AS regulation contributes to cancer progression by generating cancer-specific AS isoforms involved in tumor establishment, progression and resistance to therapeutic treatments. Paradoxically, despite the importance of AS in cancer progression, our knowledge regarding its role in tumor angiogenesis is still lacking limiting the possibility to identify more specific targets for anticancer treatments.
For the first time, we found that the AS factor Nova2 is an important post-transcriptional regulator of angiogenesis and is required for correct vascular development. Our recent results show that Nova2 is overexpressed in tumor endothelial cells of different cancers and we characterized the vascular role of a number of novel Nova2 AS targets. 
Our main goal is to characterize the impact of Nova2-dependent AS regulation in tumor angiogenesis. Our specific aims are:
1) To study the role of Nova2 during tumor angiogenesis and cancer growth;
2) To identify Nova2-regulated tumor vascular markers (Nova2-TVMs);
3) To dissect the function(s) of Nova2-TVMs.