José Gabriel Rinaldi, MD, PhD

Qualifications - Degrees

2011Doctor of Philosophy (PhD) Molecular and Cell Biology, Program of Development of Basic Science -PEDECIBA- (PhD Program).School of Science, University of the Republic, Montevideo, Uruguay. Thesis: “Functional Genomics tools in Helminth Parasites: Transgenesis and RNAi in trematodes” Director: Dr. Paul J. Brindley, Co-director: Dr. Jose F. Tort (2008-2011)

2008 Master in Science (MSc) Molecular and Cell Biology, Program of Development of Basic Science-PEDECIBA-School of Science, University of the Republic, Montevideo, Uruguay. Thesis: “Contribution to Functional Genomics in Fasciola hepatica: RNA interference”. Dissertation Director: Dr. Jose F. Tort, Co-director: Dra. Estela Castillo (2005-2008)

2001Medical Doctor (MD) School of Medicine, University of the Republic (UDELAR). Montevideo, Uruguay. (1993-2001)

Currentappointment.Research Assistant Professor, Department of Immunology, Microbiology and Tropical Medicine, School of Medicine & Health Sciences, George Washington University. Washington DC, USA. Since July 2012.

Previous appointments

2003-2013. Research Assistant in Genetics (Gº2, full time permanent position*), Department of Genetic, School of Medicine, University of the Republic (UDELAR), Uruguay. (*Permanent positions at the University in Uruguay are obtained by opposition through examination tests in the discipline, and an evaluation of the candidates´ CVs. The candidates with the higher cumulative marks are awarded the position).

2008-2012.Post Doc Scientist.Department of Immunology, Microbiology and Tropical Medicine. The George Washington University, Washington , DC. USA.

1999-2003.Demonstrator in Genetics (Gº1 permanent position), Genetics Department, School of Medicine, UDELAR. Montevideo, Uruguay

2002-2008. Clinical Assistant, General Medicine Physician. Private Health Institution: “AsistencialMédicaDepartamental de Maldonado”, Maldonado, Uruguay.

2002-2004. Fellow of the Education Ministry, Department of Genetic Toxicology and Chromosome Pathology, Biological Research Institute ‘Clemente Estable’. Montevideo, Uruguay.

Research Activities

The main interest of our group is the use of Cellular and Molecular Biology approaches to the study of medical diseases, in particular infectious diseases and neglected tropical diseases that mainly affect the most impoverished regionsof the world.In this regard our work is centered in the interrelations between parasites and their hosts, seeking for molecular mediators that would lead to potential targetsfor drug and/or vaccine development.More recently, I have become interested in the relationship between infections and cancer, more specifically between helminth parasites and cancers.

Functional genomics for helminth parasites.My interest in host/parasite interactions is focused in the development of genetic manipulation approaches and tools to elucidate the function of genes in order to more readily decipher host parasite relationships and discover new interventions. My colleagues and I – including Drs. Paul J. Brindley (GWU), Victoria Mann (GWU), José F. Tort (School of Medicine, Uruguay), and Matthew Berriman (Wellcome Trust Sanger Institute, England) - have undertaken extensive research during the past decade aimed at Functional Genomics of trematodes including schistosomes and the liver flukesFasciola hepatica andOpisthorchisviverrini.Our group has extensive experience with in vitro culture of developmental stages of these pathogens, methods and approaches to transduce cultured schistosomes with retrovirus virions and other integration competent vectors including transposons, and mouse models of schistosomiasismansoni and haematobia. I have been centrally involved in development of molecular tools for transgenesis mediated by retrovirus, conventional RNAi and vector-based RNAi in S. mansoni. In this regard, I played a key role in Dr. Paul Brindley’s NIAID sponsored study “Transduction of Schistosomamansoni by pseudotyped retrovirus” - award number RO1 AI072773, the aims of which were to develop replication incompetent Murine Leukemia Virus (MLV) vectors pseudotyped with VSVG for transduction of development stages of the schistosome and to establish retroviral vector based RNA interference . During the AI072773 award, we determined that:

1. Retroviral transgenes integrate into schistosome chromosomes;

2. Retroviral vector based RNA interference is functional in schistosomes;

3. Insulator gene sequences incorporated into the retrovirus genome protect transgenes against silencing;

4. The neoR gene – encoded in retroviral transgenes integrated into schistosome chromosomes after transduction with pseudotyped retrovirus, facilitated selection of transgenic schistosomules on the aminoglycoside antibiotic G418;

5. Vertical transmission/ germline transmission of retroviral transgene through the asexual reproduction cycle in the snail: specifically, eggs transduced with retroviral transgenes hatched, releasing miracidia which infected snails; cercariae released from these snails were transgenic, confirming germlinetransgenesis;

6. Establishment of MLV-transgenic lines of schistosomes for several asexual and sexual reproduction cycles (i.e. up to 3 generations);

7. Wide scale integration of retroviral viral transgenes throughout the genome of S. mansoni – including across all seven autosomes and the Z and W sex chromosomes, therefore indicating the potential utility of this retrovirus for random insertional mutagenesis of S. mansoni.

8. Transfer technology developed in Schistosomamansoni tothe less- well studied flukes Schistosomahaematobium and Fasciola hepatica. Accordingly we employed transfection approaches and demonstrated the presence of an active RNAi pathway inS. haematobium and F. hepatica.

These findings were novel for schistosomes, indeed novel for any parasitic worm. These findings and reviews on genetic manipulation of schistosomes have been published in highly ranked journals including The FASEB Journal, PLoS Neglected Tropical Diseases, Transgenic Research, International Journal for Parasitology and PLoS Pathogens.

Collaborations:

  • Dr. Matthew Berriman.Wellcome Trust Sanger Institute, Cambridge, England
  • Dr.SutasSuttiprapa. Department of Microbiology, Faculty of Science, Mahidol University, Bangkok, Thailand
  • Dr. José F. Tort. Department of Genetic, School of Medicine, University of the Republic, Uruguay
  • Dr. Carlos Carmona. Institute of Hygiene, School of Science, University of the Republic, Uruguay
  • Dr. Martín Cancela.Center for Biotechnology (CBiot) of the Federal University of Rio Grande do Sul (UFRGS), Brazil
  • Dr. Pablo Smircich.Laboratory of Molecular Interactions, School of Science, University of the Republic, Uruguay

Infectious-related cancers.Our group is interested in the relationship between infections and cancer, more specifically between helminth parasites and cancers. Colleagues, including Drs. Paul J. Brindley, Jeffrey M. Bethony(Microbiology, Immunology, and Tropical Medicine George Washington University, School of Medicine & Health Science, GWU)and Jason P. Mulvennaand I are developing model systems to investigate the role of Schistosomahaematobium in squamous cell carcinoma of the bladder and Opisthorchisviverrini in bile duct cancer. The research is not only focused on the basic biology of the carcinogenesis mediated by the parasites, but also on the survey for potential diagnostic and prognostic cancer biomarkers such as miRNAs. In addition, we have also started the screening for miRNA signatures as potential biomarkers in the Epstein-Barr virus-related nasopharyngeal carcinoma.

-Opisthorchisviverrini and cholangiocarcinoma (CCA).

Liver fluke infection caused by Opisthorchisviverrini is a major public health problem in Thailand and adjacent countries. In addition to infection-associated morbidity, infection with O. viverrini and the related Clonorchissinensis are unarguable risk factors for cholangiocarcinoma. Our group studies the basic biology of the host-parasite interaction focus on proteins and/or other molecular mediators derived from the liver fluke and involved in the events that would eventually lead to carcinogenesis. In addition, we have started to screen miRNA profiles in human samples that would be employed as biomarkers in the future.

Collaborations:

  • Dr. BanchobSripa.Department of Pathology, Faculty of Medicine, KhonKaen University, KhonKaen, Thailand
  • Dr. Jason P. Mulvenna.Infectious Disease and Cancer, Queensland Institute for Medical Research, Brisbane, Australia.
  • Drs. Alex Loukas and Michael Smout. Centre for Biodiscovery and Molecular Development of Therapeutics, Queensland Tropical Health Alliance, James CookUniversity. Australia

-Schistosomahaematobium and squamous cell carcinoma of the bladder (SCC)

Schistosomiasishaematobia is a major Neglected Tropical Disease (NTD) caused by infection with a water-borne parasite, a blood fluke termed Schistosomahaematobium. There are well known causative associations between this NTD and bladder cancer (squamous cell carcinoma of the bladder) and interactions between this infection and the human endocrine (hormonal) system. We investigate why this parasite causes bladder cancer, focusing on hormone like molecules, such as catechol-estrogens that the parasite release into the bladder of infected persons.

Collaborations:

  • Dr. José Manuel Correia da Costa. Center for the Study of Animal Science, ICETA, University of Porto, Portugal.CIBP – Centre for Parasite Immunology and Biology, National Institute of Health, Porto, Portugal
  • Dr. MónicaBotelho. Center for the Study of Animal Science, ICETA, University of Porto, Portugal. CIBP – Centre for Parasite Immunology and Biology, National Institute of Health, Porto, Portugal
  • Dr. NunoViale. CIQUP, Chemistry and Biochemistry Department, Faculty of Sciences, University of Porto, Portugal
  • Dr. Júlio Santos. Clínica da Sagrada Esperança, Luanda, Angola.
  • Dr. Michael H. Hsieh. Department of Urology, Stanford University School of Medicine.

-Epstein-Barr virus (EBV) and Nasopharyngeal carcinoma (NPC)

The etiology of NPC is complex, involving multiple factors, including EBV, which appears to play an oncogenic role. Up to 40% percent of NPC cases present at an advanced stage, likely due to the deep location of the tumor in the lymphatic-rich nasopharynx and the tumors propensity for early lymphatic spread. Accordingly, new biomarkers for the prognosis and guidance of early chemotherapy are desperately needed for NPC.The expression profile of microRNAs (miRNAs) in a particular cell and/or tissue (i.e. the miRNAome) has the potential to distinguish normal from malignant states and hence can be employed as biomarkers for cancer diagnosis and prognosis. Drs. Jeffrey M Bethony, Jason P. Mulvenna and I are currently working on the assembly of a signature of dysregulatedmiRNAs associated with NPC tissue by high-throughput sequence analysis of small RNAs.

Collaborations:

  • Dr. Jeffrey M. Bethony. Microbiology, Immunology, and Tropical Medicine George Washington University, School of Medicine and health Science, GWU.
  • Dr. Jason P. Mulvenna.Infectious Disease and Cancer, Queensland Institute for Medical Research, Brisbane, Australia.
  • Dr. Paul Levine. Department of Biochemistry, School of Medicine and Health Science, George Washington University.
  • Dr. Samantha Easly.Department of Pathology, School of Medicine and Health Science, George Washington University.
  • Dr. Nader Sadeghi.Medical Faculty Associates, The George Washington University, Washington.

Selected publications

  1. Nuno Vale, Maria JoãoGouveia, MónicaBotelho, BanchobSripa, SutasSuttiprapa, Gabriel Rinaldi, Paula Gomes, Paul J. Brindley and José Manuel Correia da Costa (2013) LC-MS/MS survey of oxysterols in Opisthorchisviverrini. Parasitology International 62 (2013) 535–542
  1. Botelho MC, Vale N, Gouveiac MJ, Rinaldi G, Santose J, Santosf LL, Gomes P, Brindley PJ, Correia da Costa JM (2013). Induction of tumour-like phenotypes in urothelial cells exposed to Schistosomahaematobium soluble egg antigens possibly through estrogen-DNA adducts mediated pathway. International JournalforParasitology 43(1): 17-26.
  1. Rinaldi G*, Eckert SE*, Tsai IJ*, Suttiprapa S, Kines KJ, Tort JF, Mann VH, Turner DJ, Berriman M**, Brindley PJ** (2012) Germlinetransgenesis and insertional mutagenesis in Schistosomamansoni mediated by murine leukemia virus. PLoSPathogens 2012 Jul;8(7):e1002820. Epub 2012 Jul 26. (* These authors contributed equally to this work) (** corresponding authors)
  1. Rinaldi G, Suttiprapa S, Tort JF, Folley AE, Skinner DE, Brinldey PJ (2012) An antibiotic selection marker for schistosometransgenesis. International JournalforParasitology. 2012 Jan;42(1):123-30
  1. Young ND*, Jex AR*, Li B*, Liu S, Yang L, Xiong Z, Li Y, Cantacessi C, Hall RS, Xu X, Chen F, Wu X, Zerlotini A, Oliveira G, Hofmann A, Zhang G, Fang X, Kang Y, Campbell BE, Loukas A, Ranganathan S, Rollinson D, Rinaldi G, Brindley PJ, Yang H, Wang J**, Wang J**, Gasser RB** (2012) Whole-genome sequence of Schistosomahaematobium. Nature Genetics 2012 Jan 15. doi: 10.1038/ng.1065 (* These authors contributed equally to this work) (** corresponding authors)
  1. Suttiprapa S*, Rinaldi G*, Brindley PJ (2011) Prototypic chromatin insulator cHS4 protects retroviral transgene from silencing in Schistosomamansoni. Transgenic Research doi:10.1371/journal.pntd.0000593 (* These authors contributed equally to this work)
  1. Duvoisin R*, Ayuk MA*, Rinaldi G, Suttiprapa S, Mann VH, Lee CM, Harris N, Brindley PJ (2011) Human U6 promoter drives stronger shRNA activity than its schistosomeorthologue in Schistosomamansoni and human fibrosarcoma cells. Transgenic Research doi: 10.1007/s11248-011-9548-0 (* These authors contributed equally to this work)
  1. Rinaldi G, Okatcha TI, Popratiloff A, Ayuk MA, Suttiprapa S, Mann VH, Liang Y, Lewis FA, Loukas A, Brindley PJ (2011) Genetic manipulation of Schistosomahaematobium, the neglected schistosome. PLoS Neglected Tropical Diseases 5(10): e1348.
  1. Cancela M, Ruetalo N, DellOca N, Da Silva E, Smircich P, Rinaldi G, Roche L, Carmona C, Alvarez-Valin F, Zaha A, Tort JF (2010) Survey of transcripts expressed by the invasive juvenile stage of the liver fluke Fasciola hepatica. BMC Genomics, v. 11:227
  1. Rinaldi G, Morales ME, Alrefaei YN, Cancela M, Castillo E, Dalton JP, Tort JF, Brindley PJ (2009) RNA interference targeting leucineaminopeptidase blocks hatching of Schistosomamansoni eggs. Molecular and Biochemical Parasitology, v. 167 , p. 118-126
  1. Rinaldi G, Morales ME, Cancela M, Castillo E, Brindley PJ, Tort JF (2008) Development of functional genomics tools in trematodes: RNA interference and luciferase reporter gene activity in Fasciola hepatica. PLoS Neglected Tropical Diseases, v. 2 7 , p. e260-10
  1. Cancela M, Acosta D, Rinaldi G, Silva E, Durán R, Roche L, Zaha A, Carmona C, Tort, JF (2008) A distinctive repertoire of cathepsins is expressed by juvenile invasive Fasciola hepatica. Biochimie, v. 90 10 , p. 1461-1475

Mentoring activities in the laboratory

As co-investigator in the projects mentioned above I have served as collaborator in training and assisting researchers and graduate, master and doctoral students in both the Department of Genetics, School of Medicine, UDELAR, Uruguay and in the laboratory of Paul Brindley, Department of Microbiology, Immunology and Tropical Medicine, GWU.

Students for whom I served as collaborator and advisor:

  • Dr. Hongbin Yan (PhD). Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Science. One year internship at GWU. Project: Developing functional genomic tools for parasitic helminthes. 2013-2014
  • PitchayaMatchimakul, DVM.Ph.D. Candidate in Biomedical Sciences, Faculty of Graduate School, KhonKaen University, Khonkaen,Thailand. Thesis title: Opisthorchis viverrini-Thioredoxin-1 interaction with human apoptosis signal regulatingkinase-1 (ASK-1) related anti-apoptosis mechanism in cholangiocytes. Internship at GWU 2013.
  • MPh Anne E. Folley. Master in Public Health Microbiology & Emerging Infectious Disease Program. The George Washington University. Preceptors: Drs. Gabriel Rinaldi and Paul J. Brindley. Final Project: Development of Antibiotic Selection to Facilitate Retroviral Based Transgenesis inschistosomules and eggs of Schistosomamansoni. 17 May 2013
  • Dr. NicolásDell’Oca (MD). Master in Science Student (MSc) Molecular and Cell Biology, Program of Development of Basic Science-PEDECIBA-School of Science, University of the Republic, Montevideo, Uruguay. Final Project: “Functional Genomics for the liver fluke Fasciola hepatica”. Mentor: Dr. Jose F. Tort. An internship was coordinated and Nicolás spent two months (April- June 2012) in the laboratory of Paul J. Brindle
  • BS. Danielle Skinner. PhD Student. Final Project:“ Functional studies with Schistosomamansonivasa-like gene(s)” The George Washington University, Washington DC (2013). Mentor: Dr. Paul J. Brinldey
  • MS. Ana Zeraik. PhD Student. Final Project: “Caracterização Biofísica e EstudosFuncionais das Septinas de Schistosomamansoni” Programa de Pos-Graduacao do Instituto de Fisica de Sao Carlos (IFSC), da Universidade de Sao Paulo, naarea de fisica aplicada, opcao biomolecular. Instituto de Fisica de Sao Carlos, Grupo de Biofisica molecular Sergio Mascarenhas.(2013) Mentor: Prof. Dr. Ricardo De Marco. Co-mentor: Prof. Dr. Ana Paula Ulian de Araujo
  • Dr. Tunika I. Okatcha (PhD). PhD Final Project: “Vertical transmission, longevity, and expression of piggyBac transgenes in the human blood fluke, Schistosomamansoni”. 2011, Tulane University, New Orleans, LA, USA. Mentor Dr. Paul J. Brindley
  • Dr. Yousef N. Alrefaei (PhD). PhD Final Project: “Mos1 mariner transposon based transgenesis of the human blood fluke, Schistosomamansoni”. 2011, The George Washington University, Washington DC. Tutor Dr. Paul J. Brindley
  • MS RaphaëlDuvoisin. MS Final Project: ‘Development of vector based RNA interference in Schistosomamansoni’. Master of Science (MSc) in Life Sciences and Technologies, EcolePolytechniqueFédérale de Lausanne. 2010-2011. Mentor: Nicola Harris, Co-mentor: Paul J. Brindley
  • Dr. Mary A. Ayuk (PhD). PhD Final Project “New approaches to gene knockdown in Schistosomamansoni targeting the hemoglobin proteolysis cascade”. 2011, Howard University, Washington, DC. Mentor: Dr. Clarence M. Lee (tutor), co-mentor: Dr. Paul J. Brindley
  • Dr. Kristine Kines (PhD). PhD Final Project “Retroviral mediated transgenesis of the human blood fluke, Schistosomamansoni”. 2009, Tulane University, New Orleans, LA, USA. Mentor: Dr. Paul J. Brindley
  • Dr. María E. Morales (PhD). PhD Final Project “Transposon mediated transgenesis of schistosomes”. 2007, Tulane University, New Orleans, LA, USA. Mentor: Dr. Paul J. Brindley

Teaching Activities

School of Medicine & Health Sciences, George Washington University, USA

Postgraduate teaching

Lecture “Schistosomiasis”. Tropical Infectious Diseases (TID, Micro 6292).Spring Semester of 2012, 2013. Dr. Jeffrey M Bethony. Microbiology, Immunology, and Tropical Medicine.School of Medicine and health Science.George Washington University.

Structuring, planning and organization of the semester Course Translational Molecular Biomedicine.Organizer of the course syllabus and Instructor (2013). The course will be part of the curriculum of the Proposed New Professional Science Masters Program. M.S. in Clinical and Translational Microbiology.Dept. of Microbiology, Immunology & Tropical Medicine. Health Sciences Programs

School of Medicine, University of the Republic, Uruguay

Undergraduate teaching

Lectures in the Cell Biology Courses, 1st year of Medical Doctor and Medical Technologists curricula. Themes included: Basic genetic mechanisms, Molecular genetics, Genomics, Gene regulation.

Teaching in the Genetics module of the Basic Introductory course in the Medical School.

Themes included: Molecular Basis of Genetics, Classic Genetics and Human Genetics.

Demonstrator in practical classes during the courses Cell Biology, Tissue Biology, Reproduction and Development, of the School of Medicine.

Postgraduate teaching

Teaching in Program of Development of Basic Science (PEDECIBA) and Program of Biomedical Investigation (PROINBIO) postgraduate courses:

  • Molecular Genetics and Medicine (every two years) Subject: Genomic Imprinting, Regulatory non-coding RNAs.
  • “Transgenesis and RNAi in flatworms”. Postgraduate course: Advances in the Molecular Biology and control of helminth parasites. Dra. Mara Rosenzvit. Universidad de Buenos Aires - Facultad de Medicina - Departamento de Microbiología, Parasitología e Inmunología. Buenos Aires, Argentina. October, 2011.
  • “RNAi in flatworms”. Workshop of Functional Genomics for helminth parasites. Dr. José F. Tort. Departamento de Genética, Facultad de Medicina. Montevideo, Uruguay. November, 2011

Teaching in postgraduate courses of PEDECIBA (Program of Development of Basic Science):