Ministero della Salute

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1 Ministero della Salute Direzione Generale della Ricerca e dell' Innovazione in Sanità ABSTRACT DEI PROGETTI FINANZIATI NEL2015 CON IL BANDO RICERCA FINALIZZATA - FINANZIAMENTO 2013 NELLA SEZIONE Progetti Ordinari INDICE PROGETTI CODICE RF Destinario Istituzionale Toscana TITOLO PROGETTO Seven Tesla MR imaging as preclinical biomarker in populations at risk for Parkinson disease Area Expertise Brain Disorders and Clinical Neuroscience TIPOLOGIA_RICERCA Clinico-assistenziale AREA_STRATEGICA Neurologic diseases Finanziamento Assegnato euro ,00 CODICE RF Destinario Istituzionale Istituto Superiore di Sanita' TITOLO PROGETTO Seroprevalence of Hepatitis E virus infection in Italian blood donors: a survey at national and regional level Area Expertise Population Sciences and Epidemiology TIPOLOGIA_RICERCA Biomedica AREA_STRATEGICA Finanziamento Assegnato euro Methodological, epidemiological, ,00 socio-economic, organizational, managerial emerging public health issues related to the above reported areas CODICE RF Destinario Istituzionale SAN RAFFAELE MILANO TITOLO PROGETTO NSD1 PHD fingers as potential targets for Acute Myeloid Leukemia Area Expertise Biological Chemistry and Macromolecular Biophysics TIPOLOGIA_RICERCA Biomedica AREA_STRATEGICA Oncology Finanziamento Assegnato euro ,00

2 ABSTRACT DEI PROGETTI FINANZIATI NEL2015 CON IL BANDO RICERCA FINALIZZATA - FINANZIAMENTO 2013 NELLA SEZIONE Progetti Ordinari INDICE PROGETTI CODICE RF Destinario Istituzionale IZSPLV TITOLO PROGETTO APRON: Assay for PRiONs. DEVELOPMENT OF AN ASSAY DETECTING PRIONS IN ANIMALS AND HUMANS AFFECTED WITH PRION DISORDERS IN A PRECLINICAL AND CLINICAL STAGE Area Expertise Veterinary TIPOLOGIA_RICERCA Biomedica AREA_STRATEGICA Food safety and animal safety Finanziamento Assegnato euro ,00 CODICE RF Destinario Istituzionale Piemonte TITOLO PROGETTO Pancreatic cancer therapy based on combination of DNA vaccination and PI3Kgammainhibition Area Expertise Immunology TIPOLOGIA_RICERCA Biomedica AREA_STRATEGICA Oncology Finanziamento Assegnato euro ,00 CODICE RF Destinario Istituzionale ISTITUTO TUMORI MILANO TITOLO PROGETTO MICRORNA IN PAPILLARY THYROID CARCINOMA: PATHWAYS INVOLVED AND POSSIBLE PROGNOSTIC AND THERAPEUTIC IMPACT Area Expertise TIPOLOGIA_RICERCA Oncology 1 - Basic Translational Biomedica AREA_STRATEGICA Oncology Finanziamento Assegnato euro ,00 CODICE RF Destinario Istituzionale IZSUM TITOLO PROGETTO BIOLOGICAL APPROACH TO DECONTAMINATION OF BIVALVE MOLLUSCS FROM V.PARAHAEMOLYTICUS AND SALMONELLA BY BACTERIOVORAX SPECIES. Area Expertise Veterinary TIPOLOGIA_RICERCA Biomedica AREA_STRATEGICA Food safety and animal safety Finanziamento Assegnato euro ,00

3 ABSTRACT DEI PROGETTI FINANZIATI NEL2015 CON IL BANDO RICERCA FINALIZZATA - FINANZIAMENTO 2013 NELLA SEZIONE Progetti Ordinari INDICE PROGETTI CODICE RF Destinario Istituzionale SAN RAFFAELE MILANO TITOLO PROGETTO Defining molecular targets that govern the capacity of platelets to support hepatitis B virus (HBV)-associated liver immunopathology Area Expertise Immunology TIPOLOGIA_RICERCA Biomedica AREA_STRATEGICA Infectious and immunological diseases Finanziamento Assegnato euro ,00 CODICE RF Destinario Istituzionale Toscana TITOLO PROGETTO An integrated approach to unravel the genetic causes and molecular pathogenesis of epileptogenic focal cortical dysplasia. Area Expertise Brain Disorders and Clinical Neuroscience TIPOLOGIA_RICERCA Clinico-assistenziale AREA_STRATEGICA Neurologic diseases Finanziamento Assegnato euro ,00 CODICE RF Destinario Istituzionale HUMANITAS TITOLO PROGETTO Anti-Cholinergic receptors antibodies, cardiovascular autonomic profile and dysautonomia symptoms relationships in Pure Autonomic Failure, Amyotrophic Lateral Sclerosis and Postural Orthostatic Tachycardia Syndrome: evidence for a pathophysiology based th Area Expertise Cardiovascular and Respiratory Sciences TIPOLOGIA_RICERCA Clinico-assistenziale AREA_STRATEGICA Neurologic diseases Finanziamento Assegnato euro ,00 CODICE RF Destinario Istituzionale SAN MATTEO TITOLO PROGETTO Cardiac amyloidosis: molecular mechanism and innovative therapies for a challenging aging related cardiomyopathy Area Expertise Biological Chemistry and Macromolecular Biophysics TIPOLOGIA_RICERCA Biomedica AREA_STRATEGICA Metabolic and cardiovascular diseases Finanziamento Assegnato euro ,00

4 ABSTRACT DEI PROGETTI FINANZIATI NEL2015 CON IL BANDO RICERCA FINALIZZATA - FINANZIAMENTO 2013 NELLA SEZIONE Progetti Ordinari INDICE PROGETTI CODICE RF Destinario Istituzionale ISTITUTO TUMORI MILANO TITOLO PROGETTO SELECTIVE AXILLARY LYMPH NODE DISSECTION VS COMPLETE AXILLARY DISSECTION: A RANDOMISED CLINICAL TRIAL TO ASSESS THE PREVENTION OF LYMPHEDEMA IN BREAST CANCER TREATMENT Area Expertise Surgical Sciences, Biomedical Imaging, and Bioengineering TIPOLOGIA_RICERCA Clinico-assistenziale AREA_STRATEGICA Oncology Finanziamento Assegnato euro ,00 CODICE RF Destinario Istituzionale SAN RAFFAELE MILANO TITOLO PROGETTO Rab39b mouse models: pre-clinical studies by using AMPA receptors as possible therapeutic targets to unravel the role of RAB39B in Intellectual Disability and Autism Spectrum Disorder Area Expertise Brain Disorders and Clinical Neuroscience TIPOLOGIA_RICERCA Biomedica AREA_STRATEGICA Neurologic diseases Finanziamento Assegnato euro ,00 CODICE RF Destinario Istituzionale HUMANITAS TITOLO PROGETTO The long pentraxin PTX3 in cancer: a novel player in cancer-related inflammation Area Expertise Immunology TIPOLOGIA_RICERCA Biomedica AREA_STRATEGICA Infectious and immunological diseases Finanziamento Assegnato euro ,00 CODICE RF Destinario Istituzionale MONZINO TITOLO PROGETTO Prenylcysteine Lyase as a potential novel player in atherosclerosis Area Expertise Vascular and Hematology TIPOLOGIA_RICERCA Biomedica AREA_STRATEGICA Metabolic and cardiovascular diseases Finanziamento Assegnato euro ,00

5 ABSTRACT DEI PROGETTI FINANZIATI NEL2015 CON IL BANDO RICERCA FINALIZZATA - FINANZIAMENTO 2013 NELLA SEZIONE Progetti Ordinari INDICE PROGETTI CODICE RF Destinario Istituzionale Istituto Superiore di Sanita' TITOLO PROGETTO Calcitonin oligomers as a model to study the amyloid neurotoxicity: the focal role played by lipid rafts in the prevention and cure. Area Expertise Biological Chemistry and Macromolecular Biophysics TIPOLOGIA_RICERCA Biomedica AREA_STRATEGICA Neurologic diseases Finanziamento Assegnato euro ,00 CODICE RF Destinario Istituzionale MONDINO TITOLO PROGETTO Inhibition of endocannabinoids-hydrolyzing enzymes as a new therapeutic target for migrainetreatment: studies in animal models and preliminary evaluation in humans Area Expertise Brain Disorders and Clinical Neuroscience TIPOLOGIA_RICERCA Biomedica AREA_STRATEGICA Neurologic diseases Finanziamento Assegnato euro ,00 CODICE RF Destinario Istituzionale AUXOLOGICO TITOLO PROGETTO ALS and FTD: changing paradigms in the genotype-phenotype correlation due to C9orf72 and other gene characterization Area Expertise Brain Disorders and Clinical Neuroscience TIPOLOGIA_RICERCA Clinico-assistenziale AREA_STRATEGICA Neurologic diseases Finanziamento Assegnato euro ,00 CODICE RF Destinario Istituzionale Piemonte TITOLO PROGETTO Cervical cancer screening in younger women. Area Expertise Healthcare Delivery and Methodologies TIPOLOGIA_RICERCA Clinico-assistenziale AREA_STRATEGICA Oncology Finanziamento Assegnato euro ,00

6 ABSTRACT DEI PROGETTI FINANZIATI NEL2015 CON IL BANDO RICERCA FINALIZZATA - FINANZIAMENTO 2013 NELLA SEZIONE Progetti Ordinari INDICE PROGETTI CODICE RF Destinario Istituzionale MONDINO TITOLO PROGETTO Idiopathic Normal Pressure Hydrocephalus (inph), parkinsonism and dementia: improving the accuracy of diagnosis and the patient care to reverse the symptomatology Neurodegeneration, Phenotypes and Outcome Measures Area Expertise Brain Disorders and Clinical Neuroscience TIPOLOGIA_RICERCA Clinico-assistenziale AREA_STRATEGICA Neurologic diseases Finanziamento Assegnato euro ,00 CODICE RF Destinario Istituzionale Emilia-Romagna TITOLO PROGETTO Multicenter phase II clinical study of adoptive immunotherapy with alloreactive NK cells as consolidation strategy for elderly acute myeloid leukemia patients Area Expertise Oncology 2 - Translational Clinical TIPOLOGIA_RICERCA Clinico-assistenziale AREA_STRATEGICA Oncology Finanziamento Assegnato euro ,00 CODICE RF Destinario Istituzionale Sicilia TITOLO PROGETTO Role of environment-gene interaction in etiology and promotion of pituitary tumours. Area Expertise Endocrinology, Metabolism, Nutrition and Reproductive Sciences TIPOLOGIA_RICERCA Biomedica AREA_STRATEGICA Oncology Finanziamento Assegnato euro ,00 CODICE RF Destinario Istituzionale SANTA LUCIA TITOLO PROGETTO Cell-type and subunit specific alterations of NMDA receptors in striatum at early stages of Parkinson's disease Area Expertise Brain Disorders and Clinical Neuroscience TIPOLOGIA_RICERCA Biomedica AREA_STRATEGICA Neurologic diseases Finanziamento Assegnato euro ,00

7 ABSTRACT DEI PROGETTI FINANZIATI NEL2015 CON IL BANDO RICERCA FINALIZZATA - FINANZIAMENTO 2013 NELLA SEZIONE Progetti Ordinari INDICE PROGETTI CODICE RF Destinario Istituzionale MARIO NEGRI TITOLO PROGETTO Development of a nanoparticle-based pharmacological approach for amyotrophic lateral sclerosis Area Expertise Brain Disorders and Clinical Neuroscience TIPOLOGIA_RICERCA Biomedica AREA_STRATEGICA Neurologic diseases Finanziamento Assegnato euro ,00 CODICE RF Destinario Istituzionale FATEBENEFRATELLI TITOLO PROGETTO Neuroplasticity and Alzheimer's disease: integrated approach to identify biological and neurophysiological markers. Area Expertise Brain Disorders and Clinical Neuroscience TIPOLOGIA_RICERCA Biomedica AREA_STRATEGICA Neurologic diseases Finanziamento Assegnato euro ,00 CODICE RF Destinario Istituzionale CARLO BESTA TITOLO PROGETTO Subthalamic nucleus deep brain stimulation in Tourette syndrome Area Expertise Brain Disorders and Clinical Neuroscience TIPOLOGIA_RICERCA Clinico-assistenziale AREA_STRATEGICA Neurologic diseases Finanziamento Assegnato euro ,00 CODICE RF Destinario Istituzionale CASA SOLLIEVO SOFFERENZA TITOLO PROGETTO Are genetic, inflammatory and metabolomic markers of coronary heart disease related to kidney function decline in patients with type 2 diabetes? Area Expertise Population Sciences and Epidemiology TIPOLOGIA_RICERCA Clinico-assistenziale AREA_STRATEGICA Metabolic and cardiovascular diseases Finanziamento Assegnato euro ,00

8 ABSTRACT DEI PROGETTI FINANZIATI NEL2015 CON IL BANDO RICERCA FINALIZZATA - FINANZIAMENTO 2013 NELLA SEZIONE Progetti Ordinari INDICE PROGETTI CODICE RF Destinario Istituzionale MAGGIORE TITOLO PROGETTO Effect of surgical or conservative approach in patients with adrenal incidentalomas on cardiovascular, metabolic, neuropsychological and bone manifestations: respective roles of cortisol secretion and glucocorticoid sensitivity. Area Expertise Endocrinology, Metabolism, Nutrition and Reproductive Sciences TIPOLOGIA_RICERCA Clinico-assistenziale AREA_STRATEGICA Metabolic and cardiovascular diseases Finanziamento Assegnato euro ,00 CODICE RF Destinario Istituzionale Veneto TITOLO PROGETTO The genetics of sudden cardiac death in athletes and implication for risk prevention Area Expertise Cardiovascular and Respiratory Sciences TIPOLOGIA_RICERCA Clinico-assistenziale AREA_STRATEGICA Metabolic and cardiovascular diseases Finanziamento Assegnato euro ,00 CODICE RF Destinario Istituzionale Toscana TITOLO PROGETTO LEFT VENTRICULAR HYPERTROPHY IN AORTIC VALVE DISEASE AND HYPERTROPHIC CARDIOMYOPATHY: GENETIC BASIS, BIOPHYSICAL CORRELATES AND VIRAL THERAPY MODELS Area Expertise Cardiovascular and Respiratory Sciences TIPOLOGIA_RICERCA Clinico-assistenziale AREA_STRATEGICA Metabolic and cardiovascular diseases Finanziamento Assegnato euro ,00 CODICE RF Destinario Istituzionale SAN RAFFAELE MILANO TITOLO PROGETTO Inhibition of Glycolysis by 2-Deoxy-D-Glucose as a Therapeutic Strategy for Polycystic Kidney Disease Area Expertise Digestive, Kidney and Urological Systems TIPOLOGIA_RICERCA Biomedica AREA_STRATEGICA Metabolic and cardiovascular diseases Finanziamento Assegnato euro ,00

9 ABSTRACT DEI PROGETTI FINANZIATI NEL2015 CON IL BANDO RICERCA FINALIZZATA - FINANZIAMENTO 2013 NELLA SEZIONE Progetti Ordinari INDICE PROGETTI CODICE RF Destinario Istituzionale I.E.O. TITOLO PROGETTO Role of the p21-mediated DNA-Damage Response in the immune-surveillance of leukemia stem cells Area Expertise TIPOLOGIA_RICERCA Oncology 1 - Basic Translational Biomedica AREA_STRATEGICA Oncology Finanziamento Assegnato euro ,00 CODICE RF Destinario Istituzionale I.E.O. TITOLO PROGETTO Clinical utility of a next generation sequencing-based "oncochip" for therapeutic decision in metastatic breast cancer Area Expertise Oncology 2 - Translational Clinical TIPOLOGIA_RICERCA Clinico-assistenziale AREA_STRATEGICA Oncology Finanziamento Assegnato euro ,00 CODICE RF Destinario Istituzionale I.E.O. TITOLO PROGETTO Identification of new therapeutical targets of cancer stem cells: study of the mechanistics of mitotic spindle alignment to cortical polarity in mammary stem cell asymmetric divisions Area Expertise Biological Chemistry and Macromolecular Biophysics TIPOLOGIA_RICERCA Biomedica AREA_STRATEGICA Oncology Finanziamento Assegnato euro ,00 CODICE RF Destinario Istituzionale SANTA LUCIA TITOLO PROGETTO Role of serotonin in modulating L-DOPA-induced dyskinesia Area Expertise Brain Disorders and Clinical Neuroscience TIPOLOGIA_RICERCA Biomedica AREA_STRATEGICA Neurologic diseases Finanziamento Assegnato euro ,00

10 ABSTRACT DEI PROGETTI FINANZIATI NEL2015 CON IL BANDO RICERCA FINALIZZATA - FINANZIAMENTO 2013 NELLA SEZIONE Progetti Ordinari INDICE PROGETTI CODICE RF Destinario Istituzionale Piemonte TITOLO PROGETTO Improving therapeutic appropriateness of Multiple Sclerosis treatments using biological approaches to personalize therapy and save pharmaceutical spending Area Expertise Brain Disorders and Clinical Neuroscience TIPOLOGIA_RICERCA Clinico-assistenziale AREA_STRATEGICA Neurologic diseases Finanziamento Assegnato euro ,00 CODICE RF Destinario Istituzionale OSPEDALE BAMBINO GESU' TITOLO PROGETTO Role of extracellular vesicles in bone tumour pathogenesis: implications for therapy Area Expertise Musculoskeletal, Oral and Skin Sciences TIPOLOGIA_RICERCA Biomedica AREA_STRATEGICA Innovative biotechnologies Finanziamento Assegnato euro ,00 CODICE RF Destinario Istituzionale Abruzzo TITOLO PROGETTO ASSESSMENT OF THE PATHOBIOLOGICAL ROLE, DIAGNOSTIC AND PREDICTIVE VALUE OF THE NOVEL CYTOKINE IL-30 IN PROSTATE CANCER Area Expertise TIPOLOGIA_RICERCA Oncology 1 - Basic Translational Biomedica AREA_STRATEGICA Oncology Finanziamento Assegnato euro ,00 CODICE RF Destinario Istituzionale Istituto Superiore di Sanita' TITOLO PROGETTO Connecting DNA repair and metabolic alterations of obesity in a search for predictive biomarkers Area Expertise Endocrinology, Metabolism, Nutrition and Reproductive Sciences TIPOLOGIA_RICERCA Biomedica AREA_STRATEGICA Metabolic and cardiovascular diseases Finanziamento Assegnato euro ,00

11 ABSTRACT DEI PROGETTI FINANZIATI NEL2015 CON IL BANDO RICERCA FINALIZZATA - FINANZIAMENTO 2013 NELLA SEZIONE Progetti Ordinari INDICE PROGETTI CODICE RF Destinario Istituzionale ISTITUTO TUMORI MILANO TITOLO PROGETTO Molecular characterization of pulmonary sarcomatoid carcinoma, a deadly subtype of lung cancer, for patient management Area Expertise Genes, Genomes and Genetics TIPOLOGIA_RICERCA Clinico-assistenziale AREA_STRATEGICA Oncology Finanziamento Assegnato euro ,00 CODICE RF Destinario Istituzionale Veneto TITOLO PROGETTO NETosis in atherothrombotic disorders Area Expertise Vascular and Hematology TIPOLOGIA_RICERCA Biomedica AREA_STRATEGICA Metabolic and cardiovascular diseases Finanziamento Assegnato euro ,00 CODICE RF Destinario Istituzionale Emilia-Romagna TITOLO PROGETTO Validation of a novel non-invasive technique based on real time ultrasound B-mode to assess the jugular venous pulse Area Expertise Surgical Sciences, Biomedical Imaging, and Bioengineering TIPOLOGIA_RICERCA Clinico-assistenziale AREA_STRATEGICA Metabolic and cardiovascular diseases Finanziamento Assegnato euro ,00 CODICE RF Destinario Istituzionale STELLA MARIS TITOLO PROGETTO CareToy: a smart System for early home-based intervention in infants at high risk for Cerebral Palsy Area Expertise Brain Disorders and Clinical Neuroscience TIPOLOGIA_RICERCA Clinico-assistenziale AREA_STRATEGICA Neurologic diseases Finanziamento Assegnato euro ,00

12 ABSTRACT DEI PROGETTI FINANZIATI NEL2015 CON IL BANDO RICERCA FINALIZZATA - FINANZIAMENTO 2013 NELLA SEZIONE Progetti Ordinari INDICE PROGETTI CODICE RF Destinario Istituzionale Emilia-Romagna TITOLO PROGETTO Axillary Reverse Mapping (ARM).Try to identify and spare lymphatic pathways in breast cancer surgery to prevent breast cancer related lymphedema (BCRL) Area Expertise Surgical Sciences, Biomedical Imaging, and Bioengineering TIPOLOGIA_RICERCA Clinico-assistenziale AREA_STRATEGICA Oncology Finanziamento Assegnato euro ,00 CODICE RF Destinario Istituzionale Veneto TITOLO PROGETTO Development and implant of the photovoltaic artificial retina in the pig with photoreceptor degeneration: towards the human Phase-1 experimentation Area Expertise Bioengineering Sciences and Technologies TIPOLOGIA_RICERCA Biomedica AREA_STRATEGICA Innovative biotechnologies Finanziamento Assegnato euro ,00 CODICE RF Destinario Istituzionale SANTA LUCIA TITOLO PROGETTO A novel structural and functional MRI-derived index of axonal myelination: application to MS and correlation with neurophysiology Area Expertise Brain Disorders and Clinical Neuroscience TIPOLOGIA_RICERCA Clinico-assistenziale AREA_STRATEGICA Neurologic diseases Finanziamento Assegnato euro ,00 CODICE RF Destinario Istituzionale I.E.O. TITOLO PROGETTO Assessment of the therapeutic value of targeting cancer stem cells in Numb-deficient breast cancer. Area Expertise TIPOLOGIA_RICERCA Oncology 1 - Basic Translational Biomedica AREA_STRATEGICA Oncology Finanziamento Assegnato euro ,00

13 ABSTRACT DEI PROGETTI FINANZIATI NEL2015 CON IL BANDO RICERCA FINALIZZATA - FINANZIAMENTO 2013 NELLA SEZIONE Progetti Ordinari INDICE PROGETTI CODICE RF Destinario Istituzionale MAGGIORE TITOLO PROGETTO Early atherosclerosis in patients with steatosis and with chronic hepatitis C: role of visceral adiposity, procoagulant imbalance and endothelial dysfunction in vascular damage Area Expertise Endocrinology, Metabolism, Nutrition and Reproductive Sciences TIPOLOGIA_RICERCA Clinico-assistenziale AREA_STRATEGICA Metabolic and cardiovascular diseases Finanziamento Assegnato euro ,00 CODICE RF Destinario Istituzionale DON GNOCCHI TITOLO PROGETTO Mother-child immunogenetic interactions in pregnancy and risk of Autism Spectrum Disorders Area Expertise Brain Disorders and Clinical Neuroscience TIPOLOGIA_RICERCA Biomedica AREA_STRATEGICA Neurologic diseases Finanziamento Assegnato euro ,00 CODICE RF Destinario Istituzionale SANTA LUCIA TITOLO PROGETTO The prognostic value of collateral flow in acute ischemic stroke secondary to occlusion of intracranial arteries treated by endovascular therapy. Area Expertise Brain Disorders and Clinical Neuroscience TIPOLOGIA_RICERCA Clinico-assistenziale AREA_STRATEGICA Neurologic diseases Finanziamento Assegnato euro ,00 CODICE RF Destinario Istituzionale Piemonte TITOLO PROGETTO EARLY STUDY. MULTICENTER, RANDOMIZED, CLINICAL TRIAL ON THE COMPARISON BETWEENEARLY SURGERY AND CONVENTIONAL THERAPY IN INFECTIVE ENDOCARDITIS. Area Expertise Cardiovascular and Respiratory Sciences TIPOLOGIA_RICERCA Clinico-assistenziale AREA_STRATEGICA Metabolic and cardiovascular diseases Finanziamento Assegnato euro ,00

14 ABSTRACT DEI PROGETTI FINANZIATI NEL2015 CON IL BANDO RICERCA FINALIZZATA - FINANZIAMENTO 2013 NELLA SEZIONE Progetti Ordinari INDICE PROGETTI CODICE RF Destinario Istituzionale SAN RAFFAELE MILANO TITOLO PROGETTO Identification of biological and imaging events that predict the progression of Takayasu arteritis vascular lesions Area Expertise Immunology TIPOLOGIA_RICERCA Clinico-assistenziale AREA_STRATEGICA Infectious and immunological diseases Finanziamento Assegnato euro ,00 CODICE RF Destinario Istituzionale MAGGIORE TITOLO PROGETTO Vitamin D Supplementation on Assisted Reproduction Technology (ART) outcomes: a randomized clinical controlled trial and an investigation of the involved biological mechanisms Area Expertise Endocrinology, Metabolism, Nutrition and Reproductive Sciences TIPOLOGIA_RICERCA Clinico-assistenziale AREA_STRATEGICA Environmental diseases, safety of the work place and occupational diseases Finanziamento Assegnato euro ,00 CODICE RF Destinario Istituzionale Toscana TITOLO PROGETTO Novel approaches for screening of humoral primary immunodeficiencies in adult patients Area Expertise Immunology TIPOLOGIA_RICERCA Clinico-assistenziale AREA_STRATEGICA Innovative biotechnologies Finanziamento Assegnato euro ,00 CODICE RF Destinario Istituzionale Abruzzo TITOLO PROGETTO Effects of multimodal training on cognition, biomarkers, rs-fmri and brain structural integrity in MCI patients Area Expertise Brain Disorders and Clinical Neuroscience TIPOLOGIA_RICERCA Clinico-assistenziale AREA_STRATEGICA Neurologic diseases Finanziamento Assegnato euro ,00

15 ABSTRACT DEI PROGETTI FINANZIATI NEL2015 CON IL BANDO RICERCA FINALIZZATA - FINANZIAMENTO 2013 NELLA SEZIONE Progetti Ordinari INDICE PROGETTI CODICE RF Destinario Istituzionale Emilia-Romagna TITOLO PROGETTO Olfaction as an index of conversion from MCI to AD: a longitudinal functional connectivity study Area Expertise Integrative, Functional, and Cognitive Neuroscience TIPOLOGIA_RICERCA Biomedica AREA_STRATEGICA Neurologic diseases Finanziamento Assegnato euro ,00 CODICE RF Destinario Istituzionale I.N.R.C.A. TITOLO PROGETTO Report-AGE Project: clinical and biological predictors of physical function decline in older patients with chronic cardiovascular diseases Area Expertise Biology of Development and Aging TIPOLOGIA_RICERCA Clinico-assistenziale AREA_STRATEGICA Metabolic and cardiovascular diseases Finanziamento Assegnato euro ,00 CODICE RF Destinario Istituzionale OSPEDALE BAMBINO GESU' TITOLO PROGETTO Targetting the interleukin-6 receptor as a novel therapeutic approach in Duchenne muscular dystrophy to modulate muscle inflammation and regeneration Area Expertise Musculoskeletal, Oral and Skin Sciences TIPOLOGIA_RICERCA Biomedica AREA_STRATEGICA Neurologic diseases Finanziamento Assegnato euro ,00 CODICE RF Destinario Istituzionale OSPEDALE BAMBINO GESU' TITOLO PROGETTO Distinct developmental programs of cord blood and bone marrow haematopoietic stem cells reconstitute different B-cell compartments in transplanted patients leading to transplant-specific immune impairment. Cellular and molecular characterization of transi Area Expertise Immunology TIPOLOGIA_RICERCA Biomedica AREA_STRATEGICA Infectious and immunological diseases Finanziamento Assegnato euro ,00

16 ABSTRACT DEI PROGETTI FINANZIATI NEL2015 CON IL BANDO RICERCA FINALIZZATA - FINANZIAMENTO 2013 NELLA SEZIONE Progetti Ordinari INDICE PROGETTI CODICE RF Destinario Istituzionale IZSPLV TITOLO PROGETTO No more emergencies in DNA species identification: development and harmonization of molecular and next generation methods to determine and quantify origin species in food and to discriminate frauds from unintentional contamination. Area Expertise Veterinary TIPOLOGIA_RICERCA Biomedica AREA_STRATEGICA Food safety and animal safety Finanziamento Assegnato euro ,00 CODICE RF Destinario Istituzionale Veneto TITOLO PROGETTO Targeting mitochondrial calcium handling in core myopathies: an integrative approach towards novel therapeutic strategies Area Expertise Musculoskeletal, Oral and Skin Sciences TIPOLOGIA_RICERCA Biomedica AREA_STRATEGICA Neurologic diseases Finanziamento Assegnato euro ,00 CODICE RF Destinario Istituzionale SANTA LUCIA TITOLO PROGETTO Identifying preclinical phenotypic and biological markers of Alzheimer's Disease in healthy elderly at risk subjects Area Expertise Brain Disorders and Clinical Neuroscience TIPOLOGIA_RICERCA Clinico-assistenziale AREA_STRATEGICA Neurologic diseases Finanziamento Assegnato euro ,00 CODICE RF Destinario Istituzionale IZSPLV TITOLO PROGETTO A new immunotherapy option for oral melanoma and other canine malignant tumors using a DNA vaccine coding for human chondroitin sulphate proteoglycan 4 (CSPG4), integrated with the validation of candidate gene useful for therapeutic opportunities and prog Area Expertise Veterinary TIPOLOGIA_RICERCA Biomedica AREA_STRATEGICA Oncology Finanziamento Assegnato euro ,00

17 ABSTRACT DEI PROGETTI FINANZIATI NEL2015 CON IL BANDO RICERCA FINALIZZATA - FINANZIAMENTO 2013 NELLA SEZIONE Progetti Ordinari INDICE PROGETTI CODICE RF Destinario Istituzionale S.CAMILLO TITOLO PROGETTO Modulation of visuospatial awareness during multi-tasking in right hemisphere stroke patients: towards novel behavioral and neurofunctional predictors of impairment and recovery of the attentional networks Area Expertise Integrative, Functional, and Cognitive Neuroscience TIPOLOGIA_RICERCA Biomedica AREA_STRATEGICA Neurologic diseases Finanziamento Assegnato euro ,00 CODICE RF Destinario Istituzionale Emilia-Romagna TITOLO PROGETTO A NOVEL INTEGRATED GENOMIC AND IMMUNOLOGICAL STRATEGY FOR THE THERAPY OF CHRONIC HEPATITIS B Area Expertise Immunology TIPOLOGIA_RICERCA Biomedica AREA_STRATEGICA Infectious and immunological diseases Finanziamento Assegnato euro ,00 CODICE RF Destinario Istituzionale MAGGIORE TITOLO PROGETTO Effects of maternal nutrition during pregnancy on fetal epigenetic profile: set up of a research infrastructure. Area Expertise Healthcare Delivery and Methodologies TIPOLOGIA_RICERCA Biomedica AREA_STRATEGICA Innovative biotechnologies Finanziamento Assegnato euro ,00 CODICE RF Destinario Istituzionale Umbria TITOLO PROGETTO Vitamin E, mirna and inflammation: a tunable network in Alzheimer's disease. Area Expertise Brain Disorders and Clinical Neuroscience TIPOLOGIA_RICERCA Biomedica AREA_STRATEGICA Neurologic diseases Finanziamento Assegnato euro ,00

18 ABSTRACT DEI PROGETTI FINANZIATI NEL2015 CON IL BANDO RICERCA FINALIZZATA - FINANZIAMENTO 2013 NELLA SEZIONE Progetti Ordinari INDICE PROGETTI CODICE RF Destinario Istituzionale SAN GALLICANO TITOLO PROGETTO Clinical and Experimental Pathway to Vitiligo Management Area Expertise Musculoskeletal, Oral and Skin Sciences TIPOLOGIA_RICERCA Clinico-assistenziale AREA_STRATEGICA Infectious and immunological diseases Finanziamento Assegnato euro ,00 CODICE RF Destinario Istituzionale ISTITUTO TUMORI MILANO TITOLO PROGETTO Towards precision medicine for patients with biliary tract cancers: tailored treatments based on the mutational profile detected on tumor lesions and monitored in liquid biopsies (circulating tumor cells, CTC, and circulating tumor DNA, ctdna) Area Expertise Oncology 2 - Translational Clinical TIPOLOGIA_RICERCA Clinico-assistenziale AREA_STRATEGICA Oncology Finanziamento Assegnato euro ,00 SEGUONO ABSTRACT PROGETTI FINANZIATI

19 Seven Tesla MR imaging as preclinical biomarker in populations at risk for Parkinson disease BANDO 2013 Progetti Ordinari RF RF Cosottini Mirco Clinical health care research/clinicoassistenziale Toscana LETTER OF INTENT - ABSTRACT New strategies for diagnostic, therapeutic and clinical care in Neurologic diseases Project Classification IRG: Project Classification SS: Brain Disorders and Clinical Neuroscience Clinical Neuroscience and Neurodegeneration - CNN Project Keyword 1: Project Keyword 2: Project Keyword 3: Parkinson s disease and other movement disorders (Huntington s, Dystonias, Ataxias). Magnetic resonance imaging Ultra high field magnetic resonance Project Request: Animals: Humans: X Clinical trial: The project has already been presented: Project code reference: I declare that the object/s of this application is/are under patent copyright Operative Units INSTITUTION Department/Division/Lavoratory Role in the project 1 Toscana Azienda Ospedaliero Universitaria Pisana UO Neuroradiologia 2 Toscana Azienda Ospedaliero Universitaria Pisana UO Neurologia 3 Azienda Ospedaliero Universitaria San Giovanni di Dio e Ruggi d'aragona Azienda Ospedaliero Universitaria San Giovanni di Dio e Ruggi d'aragona UO Neurologia Coordinator MR acquisition Patient recruitment Genetic analysis Patient recruitment Investigators, Institution and Role in the Project Key Personnel Institution/Org./Pos. Role in the project Birth Date 1 Ceravolo Roberto Toscana Patient recruitment 04/04/ Pellecchia Maria Teresa Azienda Ospedaliero Universitaria San Giovanni di Dio e Ruggi d'aragona Genetic analysis Patient recruitment 03/06/ /07/ / 5

20 Seven Tesla MR imaging as preclinical biomarker in populations at risk for Parkinson disease BANDO 2013 Progetti Ordinari RF RF Clinical health care research/clinicoassistenziale Cosottini Mirco Toscana Background and Significance Parkinson s disease (PD) has a long premotor period during which pathological features evolve but do not reach the threshold for presenting with motor symptoms. In this period a clinical diagnosis is not permitted and a preclinical biomarker would be advisable. Identification of subjects with increased risk to evolve to PD would allow a better understanding of disease progression, an early diagnosis even before symptom onset and a prompt treatment. More importantly, neuroprotective therapies might be most successful if given in this preclinical phase. People with the higher risk to evolve to PD are subjects carrying gene mutations for monogenic forms of PD and subjects affected by conditions associated with an increased risk of PD such as hyposmia and Rem Sleep Behaviour Disorder (RBD). Ultra-high field (UHF) MRI is a research tool that improves the image contrast and resolution, and has been tested in different neurological disorders. In PD, targeted UHF-MRI of the midbrain allows to reveal the loss of the normal structure of the substantia nigra (SN). In particular the intermediate component of the SN (compacta ventralis) and the nigrosome1 formation are not recognizable in PD patients allowing a diagnostic accuracy near to 100 % also in patients with short disease duration. Application of UHF 7-Tesla MRI to premotor PD stage could provide a marker of SN degeneration and within the population at risk, could help to identify subjects with the higher possibility to develop Specific aims Aim 1: Aim 2: Aim 3: To identify the changes of the SN anatomy in patients with genetic form of PD (Park1, Park2, Park8) and specific mutation carriers as a preclinical biomarker of disease: the main questions that will be addressed concern the SN changes in different forms of parkinsonisms (monogenic parkinsonism versus typical sporadic PD) and the timeline of the appearance of such SN alterations (monogenic parkinsonism versus gene mutation carriers). To identify the changes of the SN anatomy in subjects at risk of developing PD (RBD or hyposmia): the question addressed will concern which is the percentage of subjects with abnormal nigral aspect in a group of subjects at increased risk for PD. To evaluate longitudinally the clinical course of subjects at risk either genetic or sporadic: the question addressed concerns the potential predictive value of SN anatomy changes in the follow-up and the evaluation of risk of conversion to a clinical PD. Hypothesis: Since the dopamine loss within the SN occurs before the clinical onset of the disease and the inner structure of the SN is detectable at 7T, we hypothesize that target imaging of the SN might represent a radiological specific sign in subjects with monogenic PD forms and a biomarker of increased risk of conversion from preclinical phase to the disease in subjects at risk. Preliminary data: We described in previous works the UHF-7T MR capability to identify the inner structure of the SN and their changes in the early phase (also Hoehn&Yahr stage I) of PD with respect to healthy controls (Cosottini et al, Radiology 2014). We also demonstrated that 7T MR is well tolerated both in healthy subjects and patients with PD (Cosottini et al, Eur Radiol 2014). Preliminary unpublished data have suggested that the nigrosome changes are present also in atypical parkinsonisms as well as in two cases of parkinsonisms associated respectively with Park8 and Park2 mutation. 10/07/ / 5

21 Seven Tesla MR imaging as preclinical biomarker in populations at risk for Parkinson disease BANDO 2013 Progetti Ordinari RF RF Clinical health care research/clinicoassistenziale Cosottini Mirco Toscana Materials and Methods We will enroll the following study population: 25 patients with monogenic PD (Park1, Park2, Park8); 25 asymptomatic subjects carriers of a gene mutation involved in PD; 40 patients with hyposmia; 40 patients with REM Sleep Behaviour Disorder. All subjects will be clinically evaluated before the 7T MRI scan, to obtain a disease staging in monogenic PD patients, and to exclude mild parkinsonian signs in the population at risk. MR examinations will be performed by using a 7T scanner GE 950 MRI (GE Healthcare Medical Systems, Milwaukee, WI, USA) equipped with a 2ch-tx/32ch-rx head coil (Nova Medical, Wilmington, MA USA). All subjects will undergo a high resolution three-dimensional Susceptibility-Weighted Angiography (SWAN). The SWAN acquisition time is 4 02, the in plane resolution is 312 µm. After the scan, all subjects will be clinically evaluated at every four months to uncover the appearance of any motor signs and non motor symptoms in the population at risk. Impact and Translational Implications Identification of patients with high risk to evolve to PD would allow early diagnosis or even a preclinical detection. Since putative neuroprotective or disease modifying therapies might be more effective in the preclinical phase than when the critical threshold from preclinical to clinical manifestation has been passed, the identification of a biomarker of risk of PD is desirable. A MRI based biomarker would be an objective, not invasive new tool for early PD diagnosis and treatment planning. 10/07/ / 5

22 RF Seroprevalence of Hepatitis E virus infection in Italian blood donors: a survey at national and regional level Pisani Giulio Biomedical/Biomedica Istituto Superiore di Sanita' LETTER OF INTENT - ABSTRACT New strategies for diagnostic, therapeutic and clinical care in Methodological, epidemiological, socio-economic, organizational, managerial emerging public health issues related to the above reported areas Project Classification IRG: Project Classification SS: Population Sciences and Epidemiology Infectious Diseases, Reproductive Health, Asthma and Pulmonary Conditions - IRAP Project Keyword 1: Project Keyword 2: Project Keyword 3: The transmission and distribution of infectious, reproductive, asthma/allergy, and non-malignant pulmonary conditions in human populations in relation to person, place, time, environmental exposures, animal/insect vectors and personal characteristics or behaviors. Hepatitis E virus Blood safety Project Request: Animals: Humans: X Clinical trial: The project has already been presented: Project code reference: I declare that the object/s of this application is/are under patent copyright Operative Units INSTITUTION Department/Division/Lavoratory Role in the project 1 Istituto Superiore di Sanita' National Center for Immunobiologicals Research and Evaluation, Biological Unit 2 Istituto Superiore di Sanita' Department of Infectious, Parasitic and Immuno-mediated diseases, Viral Hepatitis Unit Coordinator of the project Coordinator of laboratory investigation and result evaluation 3 Istituto Superiore di Sanita' National Blood Center Coordinator of the Italian Blood Transfusion Centres Investigators, Institution and Role in the Project Key Personnel Institution/Org./Pos. Role in the project Birth Date 1 Bruni Roberto Istituto Superiore di Sanita' Coordinator of laboratory investigation, result evaluation and study design 26/06/ Pupella Simonetta Istituto Superiore di Sanita' Coordinator of the Italian Blood Transfusion Centres and study design 3 equestre michele Istituto Superiore di Sanita' Next Generation Sequencing and molecular analysis and result evaluation 4 Pezzotti Patrizio Istituto Superiore di Sanità Study design, statistical analysis and result evaluation 22/04/ /08/ /12/ /07/ / 5

23 RF Seroprevalence of Hepatitis E virus infection in Italian blood donors: a survey at national and regional level Pisani Giulio Biomedical/Biomedica Istituto Superiore di Sanita' Background and Significance Hepatitis E virus (HEV) can cause sporadic as well as epidemic acute hepatitis. In Europe, all autochthonous HEV infections are caused by HEV genotype 3 (gt-3) and are linked to the consumption of contaminated food. In general, HEV gt-3 infection remains asymptomatic or occurs as mild self-limited acute hepatitis. During HEV infection, the first antibody to appear is IgM at week 4, followed by IgG at week 5. Usually IgM positivity persists for 2-3 months while viremia appears at week 2 and normally lasts for 2 to 3 weeks but it can last up to 112 days. Recently, seroprevalence studies among blood donors were performed in several places in Europe and they evidenced a large heterogeneity with values of IgG positivity varying from around 5% to more than 50%. Several studies also evidenced presence of HEV IgM and HEV RNA in some sera suggesting that HEV infection in blood recipient is possible. Transfusiontransmitted risk for HEV infections may be relevant for individuals who are immunocompromised or are unable to achieve viral clearance. These patients are at risk of developing chronic HEV infection with increased mortality. Specific aims Aim 1: Aim 2: Aim 3: To estimate the IgG seroprevalence of HEV in Italian blood donors at national and regional level. Up to now there are no nationwide data about HEV prevalence in Italy. Only few and old prevalence data based on studies performed at local or regional level using first generations of ELISA kit are available. To evaluate anamnestic information from blood donors enrolled in the study, in order to identify behavioural risk factors possibly related to HEV transmission. To define the proportion of imported (due to gt-1) and autochthonous (due to gt-3) cases as well as to compare HEV strains from different Italian regions, and evaluate the zoonotic origin of autochthonous infections by comparison of human HEV sequences with sequences from animal viruses available in databases (HEV from pig and wild boar). Hypothesis: Based on recent studies and our preliminary data (see below), it is hypothesized that HEV infection in Italy may be more common than previously believed, especially in some local settings, raising the possibility of transfusion transmission risk. In order to estimate the Italian HEV prevalence, the IgG, IgM and HEV RNA detection in serum of blood donors will be evaluated. The study will involve at least 100 blood unit centers and at least 10,000 serum samples. The high number of blood unit centers is needed to take into account the likely high heterogeneity in the prevalence. In fact, we expect that, assuming that the intraclass correlation be 0.1 among donors of the same center, the estimate of the prevalence will have a 95% confidence intervals of around ±5%. Preliminary data: In a recent survey on a small blood donor population from a region of central Italy, a HEV IgG seroprevalence of 48% ( 95% CI: 43-54) was observed. Multiple binomial regression showed that eating raw dried pork liver sausage was associated with past and present infection in this region (APRR=2.11, 95% CI: 1-3). Among IgG positive samples, 2 samples (1.3%) tested positive for IgM, and one of them was also HEV-RNA positive by Real-Time PCR. Sequence analysis of a viral genome fragment amplified from this latter sample showed that the infecting virus was gt-3. A parallel blood donor survey from another region of central Italy showed quite lower IgG prevalence (9%), suggesting high heterogeneity among Italian regions. These findings prompt for a nationwide large scale study. 10/07/ / 5

24 RF Seroprevalence of Hepatitis E virus infection in Italian blood donors: a survey at national and regional level Pisani Giulio Biomedical/Biomedica Istituto Superiore di Sanita' Materials and Methods The study will consider a stratified two-stage sampling design using the blood unit (cluster) as the first stage of sampling and the donors as the second stage of sampling. Clusters will be sampled with weights proportional to the volume of blood donations performed in the last year. The sampling selection will be based on stratification by region and by randomization for the blood unit centers within each region. Voluntary blood donors within each included center will be selected for the study covering all Italian regions and after taking written consent. Serum samples will be tested for anti-hev IgG by ELISA kits. Positive samples will be tested for anti-hev IgM, presumptive for acute infection. IgM positive samples will be tested by Real-Time PCR for HEV RNA detection. The HEV genome of positive samples will be characterized by a next generation sequencing approach (Illumina MiSeq platform). All statistical analyses will be based on formulae based in the two-sampling design. Impact and Translational Implications 1) Evaluating the prevalence of HEV infection among blood donors at national and regional level and to establish the influence of age, sex, geographical origin and specific risk factors 2) These data can be used by the National Blood Center and regulatory authorities for planning future preventive interventions even at the level of different regions of the country.

25 NSD1 PHD fingers as potential targets for Acute Myeloid Leukemia BANDO 2013 Progetti Ordinari RF RF Musco Giovanna Biomedical/Biomedica Ospedale San Raffaele - Milano LETTER OF INTENT - ABSTRACT New strategies for diagnostic, therapeutic and clinical care in Oncology Project Classification IRG: Project Classification SS: Biological Chemistry and Macromolecular Biophysics Macromolecular Structure and Function C - MSFC Project Keyword 1: Project Keyword 2: Project Keyword 3: Protein-protein and protein-nucleic acid interactions, small molecule interactions with proteins and nucleic acids, and mechanisms of allostery. structure-function epigenetics Project Request: Animals: X Humans: Clinical trial: The project has already been presented: X Project code reference: RF I declare that the object/s of this application is/are under patent copyright Operative Units INSTITUTION Department/Division/Lavoratory Role in the project 1 Ospedale San Raffaele - Milano 2 Ospedale San Raffaele - Milano Genetics and Cell Biology\ Biomolecular PI NMR Unit Functional genomics of cancer/division of Molecular Oncology Head of the unit in charge of AIM2 3 IFOM - ISTITUTO FIRC DI ONCOLOGIA MOLECOLARE Proteomica funzionale Head of the unit in charge of AIM3 Investigators, Institution and Role in the Project Key Personnel Institution/Org./Pos. Role in the project Birth Date 1 Tonon Giovanni Ospedale San Raffaele - Milano Head of the unit in charge of AIM2 24/02/ Bachi Angela IFOM - ISTITUTO FIRC DI ONCOLOGIA MOLECOLARE Head of the unit in charge of AIM3 09/04/ /07/ / 6

26 NSD1 PHD fingers as potential targets for Acute Myeloid Leukemia BANDO 2013 Progetti Ordinari RF RF Biomedical/Biomedica Musco Giovanna Ospedale San Raffaele - Milano Background and Significance The Nuclear receptor-binding SET domain protein 1 (NSD1), an histone methyltransferases, is fused to the nucleoporin NUP98 in up to 16% paediatric cases of human cytogenetically-normal acute myeloid leukemia (AML). Patients presenting this translocation have a dramatic prognosis, with a median survival of few months, among the worst in leukemias, and no effective treatment available. Among the protein domains present in NSD1, a plant homeo-domain finger (PHDv) juxtaposed to a variant PHD finger (C5HCH) is crucial for the inappropriate activation of HOX genes and is required for oncogenesis. Consistent with its putative role as chromatin reader, this region binds H3K4me3 and H3K9me3 in vitro but also provides a hub for the interaction with other proteins critical for NSD1 oncogenic activity such as the transcriptional repressor NIZP1. Other methyltransferases frequently translocated in cancer, such as MLL, rely on interacting proteins as for example DOT1L and BRD4 to deregulate transcription and to unleash the cancer phenotype. Remarkably, highly-promising compounds targeting these interacting partners have recently demonstrated remarkable impact in preclinical studies. PHD domains are critical for oncogenesis. Therefore, the validation of inhibitors targeting the NSD1 PHD domain and the identification of PHD interacting proteins endowed with oncogenic potential are critical steps toward the discovery of more effective therapies for the treatment of these leukemic patients. Specific aims Aim 1: Following the reviewers' insights, we propose the following integrated aims: Structural characterization of PHDv-C5HCH domain as interaction hub for multiple binding events. We will: a) determine the structure of PHDv-C5HCH domain and characterize its interaction with modified histone H3 tails to investigate possible combinatorial reading of multiple marks involved in short-range histone crosstalk. b) screen (in silico and in vitro) for PHDv-C5HCH inhibitors. c) characterize PHDv-C5HCH/NIZP1-C2HR interaction. Aim 2: In vitro and in vivo functional assessment of pharmacological and genetic inactivation of NSD1 PHDv-C5HCH domain. a) explore the effects of the putative PHD inhibitors on NUP98-NSD1-mediated transcriptional activity, histone binding and modifications, progenitor immortalization and oncogenicity, in vitro and in vivo, using myeloid Linbone marrow progenitors. b) explore whether aminoacids involved in the binding of PHDv-C5HCH (predicted by Aim1) impact on NUP98- NSD1 activity. c) assess NUP98-NSD1 interactors oncogenic potential (see AIM3) targeting with shrna the most promising candidates in progenitor cells infected with NUP98-NSD1. Aim 3: Characterization of NSD1 interactome We will investigate the role of the PHD fingers in the recruitment of chromatin interaction partners using a SILACbased quantitative proteomic approach. a) screening of the interaction partners of NSD1 and NUP98-NSD1 in progenitor cell lines (see AIM2) b) assessment the impact of selected inhibitors (from SA1,SA2) on NUP98-NSD1 interactome Hypothesis: Dysregulation of chromatin-binding PHD fingers is emerging as powerful driving force in hematological malignancies. Combining published data and our preliminary observations, we have identified a limited set of drugs putatively binding to NSD1 PHDV-C5HCH. We propose a stringent approach that stems from a structural appraisal of NSD1, followed by biophysical, biochemical and cell biology testing, to thoroughly 10/07/ / 6

27 NSD1 PHD fingers as potential targets for Acute Myeloid Leukemia BANDO 2013 Progetti Ordinari RF RF Biomedical/Biomedica Musco Giovanna Ospedale San Raffaele - Milano explore the potential of these compounds as inhibitors of the NSD1 PHD finger oncogenicity. Based on the successful identification of compounds targeting crucial partners of rearranged proteins in other leukemias, we also propose a comprehensive study to identify and validate NUP98-NSD1 interactors, to identify druggable partners crucial for NUP98-NSD1 oncogenicity Preliminary data: 1. PHDv-C5HCH (1H/13C/15N) assignment is completed. 2. GST-pulldown experiments with unfractionated whole histones and binding assays with Histone Peptide Array suggest binding of PHDv-C5HCH to H3K4me3 and H3K9me3 3. Published GST-pull down assays suggest PHDv-C5HCH/NIZP1-C2HR interactions. C2HR-peptide is available in soluble form for biophysical interaction studies. 4. We have developed a SILAC-based quantitative proteomics protocol to study chromatin bound interactome. 5. Potential ligands identified through a virtual pre-screening 6. Effective isolation, infection and growth of myeloid Lin bone marrow progenitors from Balb/c mice Materials and Methods AIM1 Multidimensional solution NMR spectroscopy, ITC, fluorescence, analytical ultracentrifugation. Virtual Screening with databases of FDA approved molecules (NIH Clinical Collection). Validation of best hits (15) by NMR. AIM2 Retroviral infection of haematopoietic progenitor cells derived from Balb/c mouse bone marrow with mutated NUP98- NSD1. Assessment of mutations and drugs impact on binding to histone tail modifications and on HOX9 expression, in vitro and in in vivo adoptive transfer experiments AIM3 Overexpression of flagged NSD1 and NUP98-NSD1 in SILAC labelled fibroblasts. Enrichment for chromatin-bound interactors with optimized mchip protocol followed by anti-flag immunoprecipitation and MS analysis of purified interactors. SILAC based relative quantitation to discriminate between interactors and background and to evaluate interactors strength. Validation experiments in haematopoietic progenitors. IP experiments with PHD inhibitors to identify PHDv-C5HCH interactions. Impact and Translational Implications There are no effective therapies to treat leukemic patients presenting with NUP98-NSD1 translocations. The elucidation of the structural features, the functional impact, and the oncogenic interactors of the PHD domain will provide an essential springboard for the molecular understanding of the pathogenesis of this disease. Moreover, the therapeutic targeting of a PHD histone reader could unleash a new paradigm in drug development and anticancer agents 10/07/ / 6