Paola Riva
e-mail: paola.riva AT unimi.it
affiliation: Università di Milano
research area(s): Genetics And Genomics, Cancer Biology
Course:
Biomolecular Sciences
University/Istitution: Università di Milano
University/Istitution: Università di Milano
Position Title: Associated Professor in Molecular Genetics
Academic Role: Department director
EDUCATION AND TRAINING
1987 - Milan- University - Laurea in Biological Sciences
1992 - Rome - PhD in Molecular and Cellular Biology following four-year attendance to PhD course in Molecular and Cellular Biology (University of Milan)
1993-1994 - Milan - University - Post Doctoral Fellow
1997 - Milan - University - Diploma in Medical Genetics following four-year attendance to the Post Lauream School in Medical Genetics
EMPLOYMENT AND EXPERIENCE
2008 - present - Milan - University - Director of the Department of Biology and Genetics for Medical Sciences
2008 - present - Milan - University - Professor in Genetics - Single cycle degree course in Medicine
2007 - present - Milan - University - Affiliation to the Stem Cells Research Center - UniStem
2005 - Milan - University - inventor of a - Scientific didactic Instrument - Simulation of in Situ Hybridization. Patent n°. MI2005A000710, Milano 20/04/05
2005 - 2007 - Professor in the International PhD program - EMBL - Heidelberg
2003 - present - Milan - University - Professor in the PhD Course Molecular and Cellular Biology
2001 - present - Milan - University - Professor in Genetics - First level degree course in Biotecnology
2001 - present - Milan - University - Associated Professor in Molecular Genetics (BIO13 group)
1999 - 2003 - Milan/Genoa - Universities - Professor in the PhD Course Neurologia, Psichiatria and Neurogenetica
1998-present - Milan - University - Professor in Molecular Genetics - Post Lauream Specialization School in Medical Genetics
1998 - Milan - University - inventor with Dr. L. Corrado of A simple method to generate Locus-Specific probes for FISH analysis. Patent n°. MI98A 2060, Milano 24/09/98
1995 - 2001 - Milan - University - University Researcher
TECHNOLOGICAL EXPERTISE
The research activity of P.Riva Research group (Dip di Biologia e Genetica per le Scienze Mediche) deals with the human molecular genetics field by applying molecular genetics to genome structure studies, DNA and RNA analysis in both genetic diseases and cancer. More precisely there is an expertise of several years on the following techniques:
Cell culture techniques and Somatic cell genetics
Conventional and molecular cytogenetics (FISH, isotopic and single/multicolor Fluorescent in Situ
hybridization applied to metaphase, nuclei, stretched chromosomes and DNA fiber)
Molecular genetics: DNA analysis by Southern blot and Pulse Field Gel electrophoresis hybridization, PCR analysis, cloning of genomic and cDNA, cDNA selection approach, mutation screening techniques (SSCP and Heteroduplex analysis, Protein truncation test), DHPLC, direct sequencing
RNA analysis by Northern blotting, dot blotting, RT-PCR and RealTime-PCR. Functional studies by means of gene vectors for luciferase activity assays; microRNA biological studies by transfection of miRNA precursors and anti-miRNA. DNA, mRNA and protein analysis by bioinformatics tools.
FELLOWSHIPS
1988-1992 PhD Fellow in Molecular and Cellular Biology (University of Milan)
1993-1994 Post Doctoral Fellow (University of Milan)
1994-1997 Post Lauream School in Medical Genetics Fellow (University of Milan)
Academic Role: Department director
EDUCATION AND TRAINING
1987 - Milan- University - Laurea in Biological Sciences
1992 - Rome - PhD in Molecular and Cellular Biology following four-year attendance to PhD course in Molecular and Cellular Biology (University of Milan)
1993-1994 - Milan - University - Post Doctoral Fellow
1997 - Milan - University - Diploma in Medical Genetics following four-year attendance to the Post Lauream School in Medical Genetics
EMPLOYMENT AND EXPERIENCE
2008 - present - Milan - University - Director of the Department of Biology and Genetics for Medical Sciences
2008 - present - Milan - University - Professor in Genetics - Single cycle degree course in Medicine
2007 - present - Milan - University - Affiliation to the Stem Cells Research Center - UniStem
2005 - Milan - University - inventor of a - Scientific didactic Instrument - Simulation of in Situ Hybridization. Patent n°. MI2005A000710, Milano 20/04/05
2005 - 2007 - Professor in the International PhD program - EMBL - Heidelberg
2003 - present - Milan - University - Professor in the PhD Course Molecular and Cellular Biology
2001 - present - Milan - University - Professor in Genetics - First level degree course in Biotecnology
2001 - present - Milan - University - Associated Professor in Molecular Genetics (BIO13 group)
1999 - 2003 - Milan/Genoa - Universities - Professor in the PhD Course Neurologia, Psichiatria and Neurogenetica
1998-present - Milan - University - Professor in Molecular Genetics - Post Lauream Specialization School in Medical Genetics
1998 - Milan - University - inventor with Dr. L. Corrado of A simple method to generate Locus-Specific probes for FISH analysis. Patent n°. MI98A 2060, Milano 24/09/98
1995 - 2001 - Milan - University - University Researcher
TECHNOLOGICAL EXPERTISE
The research activity of P.Riva Research group (Dip di Biologia e Genetica per le Scienze Mediche) deals with the human molecular genetics field by applying molecular genetics to genome structure studies, DNA and RNA analysis in both genetic diseases and cancer. More precisely there is an expertise of several years on the following techniques:
Cell culture techniques and Somatic cell genetics
Conventional and molecular cytogenetics (FISH, isotopic and single/multicolor Fluorescent in Situ
hybridization applied to metaphase, nuclei, stretched chromosomes and DNA fiber)
Molecular genetics: DNA analysis by Southern blot and Pulse Field Gel electrophoresis hybridization, PCR analysis, cloning of genomic and cDNA, cDNA selection approach, mutation screening techniques (SSCP and Heteroduplex analysis, Protein truncation test), DHPLC, direct sequencing
RNA analysis by Northern blotting, dot blotting, RT-PCR and RealTime-PCR. Functional studies by means of gene vectors for luciferase activity assays; microRNA biological studies by transfection of miRNA precursors and anti-miRNA. DNA, mRNA and protein analysis by bioinformatics tools.
FELLOWSHIPS
1988-1992 PhD Fellow in Molecular and Cellular Biology (University of Milan)
1993-1994 Post Doctoral Fellow (University of Milan)
1994-1997 Post Lauream School in Medical Genetics Fellow (University of Milan)
SCIENTIFIC ACTIVITY
STUDY OF CHORDOMA TUMORIGENESIS ADDRESSING PROGNOSTIC MARKERS AND PHARMACOLOGICAL TARGETS IDENTIFICATION
Chordoma is a rare malignant bone tumor arising from notochord remnants, characterized by local invasiveness, variable tendency for recurrence and chemoresistance. Given the implication of apoptosis in notochord regression, we hypothesized that FAS/FASL pathway was dysregulated during notochord development/regression. The finding that most tumors didn't express FASL supports this hypothesis and prompted us to investigate the expression of the two genes during zebrafish (Danio rerio) development to address functional studies aimed at silencing these two genes.
Correlation studies between specific genetic lesions (1p36 LOH) and tumor recurrence or patients' death will be carry out with the final aim of identifying prognostic markers addressing tumor treatment.
POST TRANSCRIPTIONAL REGULATION OF CDK5R1 GENE AND POSSIBILE OATHOGENETIC IMPLICATION IN NEURODEGENERATIVE DISEASES
CDK5R1 encodes p35, an activator of cyclin-dependent kinase 5 (CDK5) and displays a very large 3'UTR, in which we identified functional post.trasncriptional regulatory AU-rich elements (ARE) and 103/107 microRNA target sites, besides the prediction of further miRNA target sites. Increased activity of CDK5 and hyperphosphorylation of Tau protein associated to microtubule in neurofibrillary tangles, as well as a descresed level of miR107 were observed in AD brains. The possible co-deregulation of miR107 and CDK5R1 in AD and the CDK5 phosphorylation activity on Tau, since now unexplored, will be investigated.
GENOTYPE-PHENOTYPE CORRELATION OF GENES AND MOLECULAR PATHWAYS INVOLVED IN NOONAN AND NEUROFIBROMATOSIS TYPE1 SYNDROMES
NF1 microdeletion syndrome accounts for 5-10% of patients affected with neurofibromatosis type 1. This genetic lesion, involving the NF1 and flanking genes, is associated to the expression of a complex clinical phenotype, including in most cases mental retardation and facial dysmorphysisms, cardiovascular anomalies, associated to this genetic lesion. Both the precise incidence of NF1 microdeletion and the occurrence of deletions with specific breakpoints are not well defined, even if most deletion breakpoints involve duplicated paralogues regions. The enrolment of further patients and their deletion characterization by FISH will allow to establish the deletion gene content by the deletion extent characterization with the final aim of carrying out genotype-phenotype correlation, fishing candidate genes for specific clinical signs. Now CDK5R1 and ADAPT2 are under investigation for mental retardation and cardiovascular abnormalities respectively.
Both classical neurofibromatosis type1 and Noonan (NS) syndrome are caused by mutations of genes involved in RAS pathway with the difference that in NS activating mutations are spread in several genes of RAS pathway, while inactivating mutations or deletions of NF1 gene, encoding neurofibromin a GTPase activating protein, causes NF1. In particular Noonan syndrome is characterized by congenital heart defects, mild mental retardation, short stature and characteristic facial features. Familial or de novo mutations in PTPN11, RAF1, SOS1, KRAS, NRAS and SHOC2 are responsible for 60-75% of the cases, thus additional genes are expected to be involved in the pathogenesis. In addition, the genotype-phenotype correlation has been hindered by the highly variable expressivity of the disease. An increasing of genotyped and clinically evaluated case numbers is necessary to identify further genes regulating RAS pathway, further mutated alleles in known genes to correlate specific genetic lesions to specific clinical signs, addressing genotype-phenotype correlation studies and improving presymptomatic diagnosis, clinical surveillance and genetic counselling, besides providing new insights on biology of RAS/RAS-related pathways.
STUDY OF CHORDOMA TUMORIGENESIS ADDRESSING PROGNOSTIC MARKERS AND PHARMACOLOGICAL TARGETS IDENTIFICATION
Chordoma is a rare malignant bone tumor arising from notochord remnants, characterized by local invasiveness, variable tendency for recurrence and chemoresistance. Given the implication of apoptosis in notochord regression, we hypothesized that FAS/FASL pathway was dysregulated during notochord development/regression. The finding that most tumors didn't express FASL supports this hypothesis and prompted us to investigate the expression of the two genes during zebrafish (Danio rerio) development to address functional studies aimed at silencing these two genes.
Correlation studies between specific genetic lesions (1p36 LOH) and tumor recurrence or patients' death will be carry out with the final aim of identifying prognostic markers addressing tumor treatment.
POST TRANSCRIPTIONAL REGULATION OF CDK5R1 GENE AND POSSIBILE OATHOGENETIC IMPLICATION IN NEURODEGENERATIVE DISEASES
CDK5R1 encodes p35, an activator of cyclin-dependent kinase 5 (CDK5) and displays a very large 3'UTR, in which we identified functional post.trasncriptional regulatory AU-rich elements (ARE) and 103/107 microRNA target sites, besides the prediction of further miRNA target sites. Increased activity of CDK5 and hyperphosphorylation of Tau protein associated to microtubule in neurofibrillary tangles, as well as a descresed level of miR107 were observed in AD brains. The possible co-deregulation of miR107 and CDK5R1 in AD and the CDK5 phosphorylation activity on Tau, since now unexplored, will be investigated.
GENOTYPE-PHENOTYPE CORRELATION OF GENES AND MOLECULAR PATHWAYS INVOLVED IN NOONAN AND NEUROFIBROMATOSIS TYPE1 SYNDROMES
NF1 microdeletion syndrome accounts for 5-10% of patients affected with neurofibromatosis type 1. This genetic lesion, involving the NF1 and flanking genes, is associated to the expression of a complex clinical phenotype, including in most cases mental retardation and facial dysmorphysisms, cardiovascular anomalies, associated to this genetic lesion. Both the precise incidence of NF1 microdeletion and the occurrence of deletions with specific breakpoints are not well defined, even if most deletion breakpoints involve duplicated paralogues regions. The enrolment of further patients and their deletion characterization by FISH will allow to establish the deletion gene content by the deletion extent characterization with the final aim of carrying out genotype-phenotype correlation, fishing candidate genes for specific clinical signs. Now CDK5R1 and ADAPT2 are under investigation for mental retardation and cardiovascular abnormalities respectively.
Both classical neurofibromatosis type1 and Noonan (NS) syndrome are caused by mutations of genes involved in RAS pathway with the difference that in NS activating mutations are spread in several genes of RAS pathway, while inactivating mutations or deletions of NF1 gene, encoding neurofibromin a GTPase activating protein, causes NF1. In particular Noonan syndrome is characterized by congenital heart defects, mild mental retardation, short stature and characteristic facial features. Familial or de novo mutations in PTPN11, RAF1, SOS1, KRAS, NRAS and SHOC2 are responsible for 60-75% of the cases, thus additional genes are expected to be involved in the pathogenesis. In addition, the genotype-phenotype correlation has been hindered by the highly variable expressivity of the disease. An increasing of genotyped and clinically evaluated case numbers is necessary to identify further genes regulating RAS pathway, further mutated alleles in known genes to correlate specific genetic lesions to specific clinical signs, addressing genotype-phenotype correlation studies and improving presymptomatic diagnosis, clinical surveillance and genetic counselling, besides providing new insights on biology of RAS/RAS-related pathways.
" Rossi E, Riegel M, Messa J, Gimelli S, Maraschio P, Ciccone R , Stroppi M, Riva P, Perrotta C, Mattina T, Baumer A, Kucinskas V, Castellan C, Schinzel A and Zuffardi O. - Duplications in addition to terminal deletions are present in a proportion of ring chromosomes. Clues to the mechanisms of formation. J Med Genet, 45:147-154, 2008
" Orzan F, Stroppi M, Venturin M, Valero MC, Hernández C, and Riva P. - Breakpoint characterization of a novel NF1 multiexonic deletion: a case showing expression of the mutated allele. Neurogenetics, 9:95 -100, 2008 DOI: 10.1007/s10048-007-0115-z
" Longoni M, Orzan F, Stroppi M, Boari N, Mortini P, Riva P. - Evaluation of 1p36 markers and clinical outcome in a skull base chordoma study. Neuro-Oncology. 10:52-60, 2008.
" Larizza L, Gervasini C, Natacci F, Riva P - Developmental abnormalities and cancer predisposition in neurofibromatosis type 1. Current Molecular Medicine, 9:634-653, 2009.
" Salvi A, Sabelli C, Moncini S, Venturin M, Arici B, Riva P, Portolani N, Giulini SM, De Petro G, Barlati S - MicroRNA-23b mediates urokinase and c-met downmodulation and a decreased migration of human hepatocellular carcinoma cells. FEBS Journal 276:2966-2982, 2009. doi:10.1111/j.1742-4658.2009.07014.x
" Martinoli E, Zuccotti GV, Pogliani L, Volonte' M, Venturin M, Fortina P, Ertel A, Redaelli S, Riva P, Dalpra' L - A Tandem Duplication of Chromosome 21 in a Newborn Showing a Phenotype Inconsistent with Down Syndrome. American Journal of Medical Genetics A, 152A: 1043-1045, 2010.
" Longoni M, Moncini S, Cisternino M, Morella IM, Ferraiuolo S, Russo S, Mannarino S, Brazzelli V, Coi P, Zippel R, Venturin M, and Riva P - Noonan Syndrome Associated With Both a New Jnk-Activating Familial SOS1 and a De Novo RAF1 Mutations. American Journal of Medical Genetics A, 152A: 2176-2184, 2010.
" Moncini S, Salvi A, Zuccotti P, Viero G, Quattrone A, Barlati S, De Petro G, Venturin M, Riva P - The Role of miR-103 and miR-107 in Regulation of CDK5R1 Expression and in Cellular Migration. PLoS ONE 6(5): e20038, 2011. doi:10.1371/journal.pone.0020038
" Orzan F, Stroppi M, Venturin M, Valero MC, Hernández C, and Riva P. - Breakpoint characterization of a novel NF1 multiexonic deletion: a case showing expression of the mutated allele. Neurogenetics, 9:95 -100, 2008 DOI: 10.1007/s10048-007-0115-z
" Longoni M, Orzan F, Stroppi M, Boari N, Mortini P, Riva P. - Evaluation of 1p36 markers and clinical outcome in a skull base chordoma study. Neuro-Oncology. 10:52-60, 2008.
" Larizza L, Gervasini C, Natacci F, Riva P - Developmental abnormalities and cancer predisposition in neurofibromatosis type 1. Current Molecular Medicine, 9:634-653, 2009.
" Salvi A, Sabelli C, Moncini S, Venturin M, Arici B, Riva P, Portolani N, Giulini SM, De Petro G, Barlati S - MicroRNA-23b mediates urokinase and c-met downmodulation and a decreased migration of human hepatocellular carcinoma cells. FEBS Journal 276:2966-2982, 2009. doi:10.1111/j.1742-4658.2009.07014.x
" Martinoli E, Zuccotti GV, Pogliani L, Volonte' M, Venturin M, Fortina P, Ertel A, Redaelli S, Riva P, Dalpra' L - A Tandem Duplication of Chromosome 21 in a Newborn Showing a Phenotype Inconsistent with Down Syndrome. American Journal of Medical Genetics A, 152A: 1043-1045, 2010.
" Longoni M, Moncini S, Cisternino M, Morella IM, Ferraiuolo S, Russo S, Mannarino S, Brazzelli V, Coi P, Zippel R, Venturin M, and Riva P - Noonan Syndrome Associated With Both a New Jnk-Activating Familial SOS1 and a De Novo RAF1 Mutations. American Journal of Medical Genetics A, 152A: 2176-2184, 2010.
" Moncini S, Salvi A, Zuccotti P, Viero G, Quattrone A, Barlati S, De Petro G, Venturin M, Riva P - The Role of miR-103 and miR-107 in Regulation of CDK5R1 Expression and in Cellular Migration. PLoS ONE 6(5): e20038, 2011. doi:10.1371/journal.pone.0020038
Project Title:
STUDY OF CHORDOMA TUMORIGENESIS ADDRESSING PROGNOSTIC MARKERS AND PHARMACOLOGICAL TARGETS IDENTIFICATION
Chordoma is an embryogenetic tumor arising from remnants of the notochord that doesn't disappear during development of vertebral bodies. The tumour is characterized by local invasiveness and variable tendency for recurrences, and it can arise at the skull base, spinal axis and sacrococcygeal level. As the apoptotic pathway, mainly mediated by FAS-FAS-L, is involved in notochord regression, we hypothesize that a dysfunction of this mechanism may be involved in chordoma tumorigenesis. The finding that most tumors didn't express FASL supports this hypothesis and prompted us to investigate the expression of the two genes during zebrafish (Danio rerio) development to address functional studies aimed at silencing these two genes.