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Click here for pictures related to the research Click here for Movies related to the research 1, 2, 3
To develop a safe and economical measles vaccine for immunization of human beings and to obtain lifelong protection against measles. SCIENTIFIC BACKGROUND Measles virus (MV) causes widespread childhood diseases, which is usually mild. The existing vaccine is of high quality and is based on the administration of live attenuated virus. It has been widely used in many parts of the world since the late sixties. In spite of these achievements, one can cite the words of the late Albert Sabin, in an interview given in 1993, who said, "In the last ten years this virus has caused 20 million childhood deaths from measles disease and related complications." In the developing world, malnutrition combined with measles virus infection is a major killer of children. The use of an experimental vaccine that showed promise in tackling the disease in the third world, Edmonston-Zagreb high titer vaccine, has been halted due to its association with high mortality in some countries. During the last 15 years, one of the major efforts in my laboratory has concerned the measles virus, and the research goals are:
A major effort is being made by a number of laboratories around the world to create and develop tools to enable gene manipulation and modification of the viral genome, followed by reconstitution of virion particles capable of infecting cells in tissue culture. Results of the combined efforts of several laboratories in work based on genetic alteration and cloning of the viral genome, along with determining its sequence, has begun to succeed, and the organization of the attenuated virus is now known in detail. Briefly, the genome of the measles virus is a single non-segmented strand of RNA of antisense orientation (negative strand virus), made up of 15,892 bases containing six "classic" genes, separted from one another by a small short stretch of bases which contain polymerase regulatory signals. The potential to code for more than six proteins is augmented in measles by various strategies employed either at the level of translation or transcription. The virus uses and RNA editing mechanism to insert a non-templated guanine residue into a specific site within the mRNA. At the level of translation, an alternate AUG initiation codon is utilized to access another reading frame and thus produce a second protein species from the same RNA molecule. All eight viral proteins are under various stages of investigation in my laboratory and are expressed from the viral cDNAs in prokaryotes or in a recombinant vaccinia virus expressing a bacteriophage polymerase in conjuction with a plasmid vector containing the measles virus CDNAs, to synthesize the viral proteins individually and in various combinations in order to elucidate specific viral functional protein-protein interactions (see attached figure). The eight viral cDNAs are cloned in their entirety and are available for cloning into a highly attenuated strain of vaccinia virus in order to create a recombinant vaccinia virus expressing the individual measles virus proteins that may subsequently be used for the purpose of vaccination. Likewise, two cDNAs encoding the highly immunogenic envelope proteins of the related morbillivirus canine distemper (CDV) are available for cloning into vaccinia virus. This may be used as a comparative system and has the added advantage that a good animal model exists for clinical testing. Click here for pictures related to the research |
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Selected Publications |
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Rozenblatt, S., Eizenberg, O., Ben-Levy, R., Lavie, V. and Bellini, W.J. (1985) Sequence homology within the morbilliviruses. J Virol,53: 684-690. medline Rozenblatt, S., Eizenberg, O., Englund, G. and Bellini, W.J. (1985) Cloning and characterization of DNA complementary to the canine distemper virus mRNA encoding matrix, phosphoprotein, and nucleocapsid protein. J Virol,53: 691-694. medline Richardson, C.D., Berkovich, A., Rozenblatt, S. and Bellini, W.J. (1985) Use of antibodies directed against synthetic peptides for identifying cDNA clones, establishing reading frames, and deducing the gene order of measles virus. J Virol,54: 186-193. medline Bellini, W.J., Englund, G., Rozenblatt, S., Arnheiter, H. and Richardson, C.D. (1985) Measles virus P gene codes for two proteins. J Virol,53: 908-919. medline Haase, A.T., Gantz, D., Eble, B., Walker, D., Stowring, L., Ventura, P., Blum, H., Wietgrefe, S., Zupanic, M., Tourellotte, W., Gibbs, C.J. Jr., Norrby, F., and Rozenblatt, S. (1985) The natural history of restricted synthesis and expression of measles virus genes in subacute sclerosing panencephalitis. Proc. Natl. Acad. Sci. USA,82: 3020-3024. medline Fournier, J.G., Tardieu, M., Lebon, P., Robain, O., Ponsot, G., Rozenblatt, S. and Bouteille, M. (1985) Detection of measles virus RNA in lymphocytes from peripheral-blood and brain perivascular infiltrates of patients with subacute sclerosing panencephalitis. N Engl J Med,313: 910-915. medline Shapshak, P., Tourtellote, W., Nakamura, S., Graves, M., Darvish, M., Hoffman, D., Walsh, M., Farreed, G., Schmid, P, Heinsmann, C., Shidu, K., Bedows, E., Rozenblatt, S., Berry, K., and Hawkins, S. (1985) Subacute sclerosing panencephalitis: Measles virus matrix protein nucleic acid sequences detected by in situhybridization. Neurology,35: 1605-1609. medline Bellini, W.J., Englund, G., Richardson, C.D., Rozenblatt, S. and Lazzarini, R.A. (1986) Matrix genes of measles virus and canine distemper virus: cloning, nucleotide sequences, and deduced amino acid sequences. J Virol,58: 408-416. medline Fournier, J.G., Lebon, P., Bouteille, M., Goutieres, F. and Rozenblatt, S. (1986) Subacute sclerosing panencephalitis: detection of measles virus RNA in appendix lymphoid tissue before clinical signs. Br Med J (Clin Res Ed),293: 523-524. medline Fourneir, J., Tardieu, M., Lebon, P., Robain, O., Ponsot, G., Rozenblatt, S., and Bouteille, M. (1986) Detection of measles virus genetic information in SSPE lymphocytes by in situ hybridization. In: Subacute sclerosing panencephalitis, edited by Bergamini, F., Defanti, C., Ferrante, P. Excerpta Medica:319-322 Basle, M.F., Fournier, J.G., Rozenblatt, S., Rebel, A. and Bouteille, M. (1986) Measles virus RNA detected in Paget's disease bone tissue by in situ hybridization. J Gen Virol,67: 907-913. medline Cattaneo, R., Schmid, A., Rebmann, G., Baczko, K., Ter Meulen, V., Bellini, W.J., Rozenblatt, S. and Billeter, M.A. (1986) Accumulated measles virus mutations in a case of subacute sclerosing panencephalitis: interrupted matrix protein reading frame and transcription alteration. Virology,154: 97-107. medline Huber, M., Garfinkel, L., Gitler, C., Mirelman, D., Revel, M. and Rozenblatt, S. (1987) Entamoeba histolytica: cloning and characterization of actin cDNA. Mol Biochem Parasitol,24: 227-235. medline Huber, M., Garfinkel, L., Gitler, C., Mirelman, D., Revel, M. and Rozenblatt, S. (1988) Nucleotide sequence analysis of an Entamoeba histolytica ferredoxin gene. Mol Biochem Parasitol,31: 27-33. medline Fournier, J.G., Gerfaux, J., Joret, A.M., Lebon, P. and Rozenblatt, S. (1988) Subacute sclerosing panencephalitis: detection of measles virus sequences in RNA extracted from circulating lymphocytes. Br Med J (Clin Res Ed),296: 684. medline Garfinkel, L.I., Giladi, M., Huber, M., Gitler, C., Mirelman, D., Revel, M. and Rozenblatt, S. (1989) DNA probes specific for Entamoeba histolytica possessing pathogenic and nonpathogenic zymodemes. Infect Immun,57: 926-931. medline Huber, M., Koller, B., Gitler, C., Mirelman, D., Revel, M., Rozenblatt, S. and Garfinkel, L. (1989) Entamoeba histolytica ribosomal RNA genes are carried on palindromic circular DNA molecules. Mol Biochem Parasitol,32: 285-296. medline Arango, R., Rozenblatt, S. and Sharon, N. (1990) Cloning and sequence analysis of the Erythrina corallodendron lectin cDNA. FEBS Lett,264: 109-111. medline Mirelman, D., Bracha, R., Rozenblatt, S. and Garfinkel, L.I. (1990) Repetitive DNA elements characteristic of pathogenic Entamoeba histolytica strains can also be detected after polymerase chain reaction in a cloned nonpathogenic strain. Infect Immun,58: 1660-1663. medline De Meester, F., Bracha, R., Huber, M., Keren, Z., Rozenblatt, S. and Mirelman, D. (1991) Cloning and characterization of an unusual elongation factor-1 alpha cDNA from Entamoeba histolytica. Mol Biochem Parasitol,44: 23-32. medline Arango, R., Adar, R., Rozenblatt, S. and Sharon, N. (1992) Expression of Erythrina corallodendron lectin in Escherichia coli. Eur J Biochem,205: 575-581. medline Petter, R., Rozenblatt, S., Nuchamowitz, Y. and Mirelman, D. (1992) Linkage between actin and ribosomal protein L21 genes in Entamoeba histolytica. Mol Biochem Parasitol,56: 329-333. medline Petter, R., Rozenblatt, S., Nuchamowitz, Y. and Mirelman, D. (1992) Chromosome walk in Entamoeba histolytica: the gene encoding for ribosomal protein L21 neighbors one of the actin genes. Arch Med Res,23: 45-48. medline Petter, R., Rozenblatt, S., Schechtman, D., Wellems, T.E. and Mirelman, D. (1993) Electrophoretic karyotype and chromosome assignments for a pathogenic and a nonpathogenic strain of Entamoeba histolytica. Infect Immun,61: 3574-3577. medline Arango, R., Rodriguez-Arango, E., Adar, R., Belenky, D., Loontiens, F.G., Rozenblatt, S. and Sharon, N. (1993) Modification by site-directed mutagenesis of the specificity of Erythrina corallodendron lectin for galactose derivatives with bulky substituents at C-2. FEBS Lett,330: 133-136. medline Petter, R., Moshitch, S., Rozenblatt, S., Nuchamowitz, Y. and Mirelman, D. (1994) Characterization of two distinct gene transcripts for ribosomal protein L21 from pathogenic and nonpathogenic strains of Entamoeba histolytica. Gene,150: 181-186. medline Mokady, O., Rozenblatt, S., Graur, D. and Loya, Y. (1994) Coral-host specificity of Red Sea Lithophaga bivalves: interspecific and intraspecific variation in 12S mitochondrial ribosomal RNA. Mol Mar Biol Biotechnol,3: 158-164. medline Stern, L.B., Greenberg, M., Gershoni, J.M. and Rozenblatt, S. (1995) The hemagglutinin envelope protein of canine distemper virus (CDV) confers cell tropism as illustrated by CDV and measles virus complementation analysis. J Virol,69: 1661-1668. medline Nussbaum, O., Broder, C.C., Moss, B., Stern, L.B., Rozenblatt, S. and Berger, E.A. (1995) Functional and structural interactions between measles virus hemagglutinin and CD46. J Virol,69: 3341-3349. medline Wyatt, L.S., Moss, B. and Rozenblatt, S. (1995) Replication-deficient vaccinia virus encoding bacteriophage T7 RNA polymerase for transient gene expression in mammalian cells. Virology,210: 202-205. medline Adar, R., Streicher, H., Rozenblatt, S. and Sharon, N. (1997) Synthesis of soybean agglutinin in bacterial and mammalian cells. Eur J Biochem,249: 684-689. medline Mokady, O., Loya, Y., Achituv, Y., Geffen, E., Graur, D., Rozenblatt, S. and Brickner, I. (1999) Speciation versus phenotypic plasticity in coral inhabiting barnacles: Darwin's observations in an ecological context. J Mol Evol,49: 367-375. medline Stittelaar, K.J., Wyatt, L.S., de Swart, R.L., Vos, H.W., Groen, J., van Amerongen, G., van Binnendijk, R.S., Rozenblatt, S., Moss, B. and Osterhaus, A.D. (2000) Protective immunity in macaques vaccinated with a modified vaccinia virus Ankara-based measles virus vaccine in the presence of passively acquired antibodies. J Virol,74: 4236-4243. medline Zhu Y, Rota
P, Wyatt L, Tamin A, Rozenblatt S, Lerche N, Moss
B, Bellini W, McChesney M. (2000). Evaluation of recombinant
vaccinia virus--measles vaccines in infant rhesus
macaques with preexisting measles antibody. Myers R, Frenzke M, Greiner S, Harvey M, Soeffker D, Abraham K, Shaw A, Rozenblatt S, Peng KW, Russell S. (2003) Comparative efficacy of fusogenic measles, mumps, and vaccinia vectors against ovarian cancer xenografts. MOLECULAR THERAPY 7 (5): 343 Part 2. Myers R, Greiner S, Harvey M, Soeffker D, Frenzke M, Abraham K, Shaw A, Rozenblatt S, Federspiel MJ, Russell SJ, Peng KW. (2005) Oncolytic activities of approved mumps and measles vaccines for therapy of ovarian cancer. Cancer Gene Ther,12(7):593-9. medline Yakubov E, Rechavi G, Rozenblatt S, Givol D. (2010) Reprogramming of human fibroblasts to pluripotent stem cells using mRNA of four transcription factors. Biochem Biophys Res Commun.394(1):189-93. medline
Garfinkel, L., Giladi, M., Huber, M., Gitler, C., Mirelman, D., Revel, M., and Rozenblatt, S. (1991) Sexually Transmitted Diseases. Year Book of Infectious Diseases published by Mosby Year Book, Inc. P. 295.
Assay for
Amoebas (DNA Probes) (T/7111)
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