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Microsoft word - linee di ricerca sezione biochimica clinica - gruppo lucarelli, ferraguti, ceci, strom

Marco Lucarelli – Associate Professor
Giampiero Ferraguti - Researcher
Fabrizio Ceci - Researcher
Roberto Strom – Full Professor
Cystic Fibrosis: molecular diagnostics, genotype – phenotype relationship and therapeutic

Cystic Fibrosis (CF), the most common monogenic disease in Caucasians, is caused by mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. CF clinical manifestations are highly variable, spanning from fatal severe (poly-symptomatic) forms with heavy respiratory failure to oligo- or mono-symptomatic forms limited to some organs or apparatus. The relationship between genotype and phenotype in CF is not clear. This uncertainty affects diagnostic, prognostic and therapeutic aspects. We address to this topic by two different approaches. The first approach is the extended mutational study of CF patients with different clinical forms of CF. The results obtained are focused on the population specificity of mutational patterns, operative characteristics of genetic tests, prevalence of complex alleles (with two or more mutations in cis on the same allele), functional characterization of mutations found, relationship between mutated genotypes and residual functionality of CFTR, as well as between the residual functionality of CFTR and final clinical manifestations. The second approach is based on the use of cellular models of normal and CF epithelia, to study the Epithelial Na+ channel (ENaC), partially repressed by the wild-type CFTR but deregulated in presence of a mutated CFTR. The aims of these studies are the analysis of the mechanism(s) of coordinated transcription of ENaC genes and of ENaC - CFTR interaction, in physiology and pathology, as well as the evaluation of therapeutic approaches of ENaC expression downregulation and activity attenuation by epigenetics and anti-proteolitic manipulations. Overall, these studies will produce an enhancement of the comprehension of genotype-phenotype relationship in both atypical and typical forms of CF, as well as of the molecular mechanism of action of molecular lesions found. In addition, it seems possible to identify ENaC as a new therapeutic target and its modulation as a new strategy for CF cure. The gene therapy approach of Small Fragment Homologous Replacement (SFHR): the
influence of epigenetics, DNA repair and cell cycle pathways.

The aim of this project is to clarify the molecular mechanisms of recognition of cell invasion by exogenous DNA, possibly underlying the SFHR gene targeting approach. The SFHR is able to stably modify a genomic sequence by homologous replacement of a small DNA fragment, by a still poorly understood molecular mechanism. The modification is inheritable, physiologically expressed and long-term maintained. The use of SFHR is however limited by a low and variable frequency of correction. This project will focus on the relationship between SFHR and chromatin structure, DNA methylation, DNA repair and cell cycle pathways. The reciprocal influence of SFHR and these 4 main biochemical pathways will be studied, in a reporter cellular system of mouse embryonic fibroblasts, in a differentiated human cellular model of Cystic Fibrosis and in a Spinal Muscular Atrophy mouse embryonic stem cell model. Drugs acting on specific target mechanisms and single-gene targeting will be also used to dissect the pathways and to manipulate SFHR efficiency. The selection of strategies aimed to increase SFHR efficiency will open up new perspective for SFHR therapeutic applications, using differentiated and stem cells as targets, for in vivo and ex vivo treatments of inherited diseases. The role of CpG and non-CpG DNA demethylation dynamics in transcriptional control.
The dynamics and structural patterns of DNA methylation are poorly characterized, particularly for genes without CpG islands and low CpG density. Little is known about the relevance of CpG to the non-CpG methylation equilibrium and the role of active demethylation in transcriptional modulation. The main objective of this project is the study of CpG and non-CpG methylation interplay and dynamics, and of their functional role, both at single-gene and at the genome-wide level. These studies are performed in different mouse experimental models which, as preliminarily assessed for specific target genes, will encompass distinct patterns of DNA methylation and gene expression: 1) the C2C2 muscle satellite cell line (and selected clones), in course of differentiation; 2) embryonic muscle and brain; 3) embryonic neural stem cells in course of differentiation. At single-gene level, particular attention is paid to genes relevant for muscle differentiation, whereas at genome-wide level experimental data will be collected for CpG and non-CpG dinucleotides within the whole mouse genome. The subsequent analyses will be mainly pointed to sequences relevant for transcriptional control. Mechanisms involved in the control of cell differentiation and proliferation through inhibition
of choline-phospholipid pathways.

Enzymes of choline-phospholipids pathways, namely phosphatidylcholine (PC) – specific phospholipase C and sphingomyelin synthase, have been found to be involved in cellular processes such as proliferation, differentiation and apoptosis. Preliminary experiments have shown that, apart from the effects that can be due to mere diacylglycerol release or ceramide utilization, at least one of the enzymes of these metabolic pathways undergoes, concomitantly to the perturbations of the cell cycle and/or of the expression of tissue-specific genes, a translocation to the nucleus. The aim of our investigations is therefore to clarify the possible correlation, at least on a time-scale basis, between the events that, upon activation or inhibition of these enzymes, occur within the cell membrane and/or in intracellular organelles, and those that, at the DNA and/or at the chromatin level, modify the expression of specific genes involved in the regulation of cell proliferation, differentiation or in the shift toward apoptosis. Molecular diagnostics of the low HDL syndrome
Atherogenic dyslipidemia (AD) is characterized by altered lipid levels associated to cardiovascular risk. The molecular diagnostics approach to the low HDL syndrome is difficult because of the involvement of several genes in this particular AD. It has been recognized that this lipid profile has a genetic base and familial clustering, but no data are available on its prevalence in childhood. We have been studying a pediatric case series characterized by low levels of HDL cholesterol (< 40 mg / dl). The aim is to characterize the mutational pattern of several genes possibly involved in the pediatric low HDL syndrome and to evaluate whether this AD in children is correlated to some similar AD in their parents. The study of a pediatric case series may also reveal useful to minimize the influence of environmental variables on lipid levels. Also the optimization of automated laboratory approaches allowing high throughput in mutational search is within the aims of this project. The genes being analyzed so far are those coding for: lipoprotein lipase (LPL), apolipoprotein AI (ApoA1), lecithin-cholesterol acyltransferase (LCAT), ATP-binding cassette transporter A1 (ABCA1). Serotonin transporter and alcohol dependence.
Genetic basis of alcohol dependence (AD) are well established. Different studies have underlined the involvement of genetic variants concerning not only ethanol metabolism, but also the neurobiology of addiction and the pathways of reward circuits. Serotonin transporter (5-HTT), molecular target of many antidepressant drugs, plays a key role in regulating serotonergic neurotransmission and has been associated with many different pathologies, including alcoholism, obsessive-compulsive disorders, major depression and other psychiatric diseases. Transcriptional regulation of serotonin transporter depends not only on epigenetic modifications but also on single nucleotide polymorphisms (SNP) affecting transcription factors and micro RNAs binding sites. These sequence variations are also involved in the pharmacological response to molecules that have 5-HTT as target. Aim of our study is to compare the expression of 5-HTT between a population of alcoholics and a matched control group and to evaluate a possible role of SNPs, known to affect the serotonin transporter expression, in determining a potentially different expression of 5-HTT between these two populations. Schippa S., Iebba V., Santangelo F., Gagliardi A., De Biase R.V., Stamato A., Bertasi S., Lucarelli M., Conte M.P., Quattruci S. Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) allelic variants relate to shifts in faecal microbiota of Cystic Fibrosis patients. PLoS One (2013) 8(4): e61176. IF2011 = 4.092 Lucarelli M., Pierandrei S., Bruno S.M., Strom R. The genetics of CFTR: genotype – phenotype relationship, diagnostic challenge and therapeutic implications. In “Cystic Fibrosis – Renewed hopes through research”, Intech open access publisher (2012) Chap. 5, pp. 91 – 122. Pascale E., Lucarelli M., Passarelli F., Butler R.H., Tamellini A., Addessi E., Visalberghi E., Manciocco A., Vitale A., Laviola G. Monomorphic region of the serotonin transporter promoter gene in new world monkeys. American Journal of Primatology (2012) 74(11):1028-1034. IF2011 = 2.221 Luchetti A., Filareto A., Sanchez M., Ferraguti G., Lucarelli M., Novelli G., Sangiuolo F., Malgieri A. Small Fragment Homologous Replacement: evaluation of factors influencing modification efficiency in an eukaryotic assay system. PLoS One (2012) 7(2):e30851 IF2011 = 4.092 Ferraguti G., Pierandrei S., Bruno S.M., Ceci F., Strom R., Lucarelli M. A template for mutational data analysis of the CFTR gene. Clinical Chemistry and Laboratory Medicine (2011) 49(9):1447-1451. IF2011 = 2.150 Fuso A., Ferraguti G., Grandoni F., Ruggeri R., Scarpa S., Strom R., Lucarelli M. Early demethylation of non-CpG, CpC-rich, elements in the myogenin 5'-flanking region: a priming effect on the spreading of active demethylation? Cell Cycle (2010) 9(19):3965-3976. IF2010 = 4.999 Lucarelli M., Narzi L., Pierandrei S., Bruno S.M., Stamato A., d’Avanzo M., Strom R., Quattrucci S. A new complex allele of the CFTR gene partially explains the variable phenotype of the L997F mutation. Genetics in Medicine (2010) 12(9):548-555. IF2010 = 5.280 Auriche C., Di Domenico E.G., Pierandrei S., Lucarelli M., Castellani S., Conese M., Melani R., Zegarra-Moran O., Ascenzioni F. CFTR expression and activity from the human CFTR locus in BAC vectors, with regulatory regions, isolated by a single step procedure. Gene Therapy (2010) 17(11):1341-1354. IF2010 = 4.538 Elia J., Delfino M., Imbrogno N., Capogreco F., Lucarelli M., Rossi T., Mazzilli F. Human semen hyperviscosity: prevalence, pathogenesis and therapeutic aspects. Asian Journal of Andrology (2009) 11(5):609-615. IF2009 = 1.688 Perrone G., Capri O., Galoppi P., Brunelli R., Bevilacqua E., Ceci F., Ciarla M.V., Strom R. Effects of either tibolone or continuous combined transdermal estradiol with medroxyprogesterone acetate on coagulatory factors and lipoprotein(a) in menopause. Gynecologic and Obstetric Investigation (2009) 68(1):33-39. I.F.2009 = 1.045 Narzi L., Ferraguti G., Stamato A., Narzi F., Valentini S.B., Lelli A., Delaroche I., Lucarelli M., Strom R., Quattrucci S. Does cystic fibrosis neonatal screening detect atypical CF forms? Extended genetic characterization and 4-year clinical follow-up. Clinical Genetics (2007) 72(1):39–46. IF2007 = 3.181



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