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  • Gene-microarray analysis of multiple sclerosis lesions yields new targets validated in autoimmune encephalomyelitis NATURE MEDICINE Lock, C., Hermans, G., Pedotti, R., Brendolan, A., Schadt, E., Garren, H., Langer-Gould, A., Strober, S., Cannella, B., Allard, J., Klonowski, P., Austin, A., Lad, N., Kaminski, N., GALLI, S. J., Oksenberg, J. R., Raine, C. S., Heller, R., Steinman, L. 2002; 8 (5): 500-508

    Abstract

    Microarray analysis of multiple sclerosis (MS) lesions obtained at autopsy revealed increased transcripts of genes encoding inflammatory cytokines, particularly interleukin-6 and -17, interferon-gamma and associated downstream pathways. Comparison of two poles of MS pathology--acute lesions with inflammation versus 'silent' lesions without inflammation--revealed differentially transcribed genes. Some products of these genes were chosen as targets for therapy of experimental autoimmune encephalomyelitis (EAE) in mice. Granulocyte colony-stimulating factor is upregulated in acute, but not in chronic, MS lesions, and the effect on ameliorating EAE is more pronounced in the acute phase, in contrast to knocking out the immunoglobulin Fc receptor common gamma chain where the effect is greatest on chronic disease. These results in EAE corroborate the microarray studies on MS lesions. Large-scale analysis of transcripts in MS lesions elucidates new aspects of pathology and opens possibilities for therapy.

    View details for DOI 10.1038/nm0502-500

    View details for PubMedID 11984595

  • The influence of the proinflammatory cytokine, osteopontin, on autoimmune demyelinating disease SCIENCE Chabas, D., Baranzini, S. E., Mitchell, D., Bernard, C. C., Rittling, S. R., Denhardt, D. T., Sobel, R. A., Lock, C., Karpuj, M., Pedotti, R., Heller, R., Oksenberg, J. R., Steinman, L. 2001; 294 (5547): 1731-1735

    Abstract

    Multiple sclerosis is a demyelinating disease, characterized by inflammation in the brain and spinal cord, possibly due to autoimmunity. Large-scale sequencing of cDNA libraries, derived from plaques dissected from brains of patients with multiple sclerosis (MS), indicated an abundance of transcripts for osteopontin (OPN). Microarray analysis of spinal cords from rats paralyzed by experimental autoimmune encephalomyelitis (EAE), a model of MS, also revealed increased OPN transcripts. Osteopontin-deficient mice were resistant to progressive EAE and had frequent remissions, and myelin-reactive T cells in OPN-/- mice produced more interleukin 10 and less interferon-gamma than in OPN+/+ mice. Osteopontin thus appears to regulate T helper cell-1 (TH1)-mediated demyelinating disease, and it may offer a potential target in blocking development of progressive MS.

    View details for Web of Science ID 000172307400049

    View details for PubMedID 11721059

  • Microarrays: biotechnology's discovery platform for functional genomics TRENDS IN BIOTECHNOLOGY Schena, M., Heller, R. A., Theriault, T. P., Konrad, K., Lachenmeier, E., Davis, R. W. 1998; 16 (7): 301-306

    Abstract

    Advances in microarray technology enable massive parallel mining of biological data, with biological chips providing hybridization-based expression monitoring, polymorphism detection and genotyping on a genomic scale. Microarrays containing sequences representative of all human genes may soon permit the expression analysis of the entire human genome in a single reaction. These 'genome chips' will provide unprecedented access to key areas of human health, including disease prognosis and diagnosis, drug discovery, toxicology, aging, and mental illness. Microarray technology is rapidly becoming a central platform for functional genomics.

    View details for Web of Science ID 000074546900005

    View details for PubMedID 9675914

  • Parallel human genome analysis: Microarray-based expression monitoring of 1000 genes PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Schena, M., Shalon, D., Heller, R., Chai, A., Brown, P. O., Davis, R. W. 1996; 93 (20): 10614-10619

    Abstract

    Microarrays containing 1046 human cDNAs of unknown sequence were printed on glass with high-speed robotics. These 1.0-cm2 DNA "chips" were used to quantitatively monitor differential expression of the cognate human genes using a highly sensitive two-color hybridization assay. Array elements that displayed differential expression patterns under given experimental conditions were characterized by sequencing. The identification of known and novel heat shock and phorbol ester-regulated genes in human T cells demonstrates the sensitivity of the assay. Parallel gene analysis with microarrays provides a rapid and efficient method for large-scale human gene discovery.

    View details for Web of Science ID A1996VL33300017

    View details for PubMedID 8855227

    View details for PubMedCentralID PMC38202

  • MECHANISMS OF TUMOR-NECROSIS-FACTOR CYTOTOXICITY AND THE CYTOTOXIC SIGNALS TRANSDUCED BY THE P75-TUMOR NECROSIS FACTOR-RECEPTOR CIRCULATORY SHOCK Reid, T., Louie, P., Heller, R. A. 1994; 44 (2): 84-90

    Abstract

    We have here provided evidence that TNF mediated cytotoxicity is genetically, pharmacologically, and temporally distinct from the cytotoxicity mediated by TNF/CHX. Most studies on TNF cytotoxicity have been done by the combined use of TNF/CHX. The relevance of this approach to the physiological mechanisms underlying cytotoxicity by TNF alone is at present unclear. We have described a system in which overexpression of the p75-TNFR causes TNF-resistant cells to become TNF-sensitive. These cells are killed by TNF alone in a very short period of time and they are a useful system to study the mechanism of TNF-cytotoxicity.

    View details for Web of Science ID A1994QF21800007

    View details for PubMedID 7743605

  • REGULATION OF CARBAMOYL PHOSPHATE SYNTHETASE-ASPARTATE TRANSCARBAMOYLASE-DIHYDROOROTASE GENE-EXPRESSION IN GROWING AND ARRESTED CELLS JOURNAL OF BIOLOGICAL CHEMISTRY Liao, W. S., Heller, R., Green, P., Stark, G. R. 1986; 261 (33): 5577-5581
  • DEVELOPMENT OF MONOCLONAL-ANTIBODIES TO "3-HYDROXY-3-METHYLGLUTARYL-COENZYME A REDUCTASE BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS Heller, R. A., Hoy, P., Jones, P. P. 1982; 106 (2): 412-421

    View details for Web of Science ID A1982NS02900025

    View details for PubMedID 7104002

  • ACTIVATION OF PURIFIED 3-HYDROXY-3-METHYLGLUTARYL-COA REDUCTASE BY PHOSPHOLIPIDS BIOCHIMICA ET BIOPHYSICA ACTA Berde, C. B., Heller, R. A., Simoni, R. D. 1977; 488 (1): 112-120

    Abstract

    3-Hydroxy-3-methylglutaryl-CoA reductase (HMG-CoA reductase), the enzyme that catalyzes the rate-limiting step in cholesterol biosynthesis, has been purified by two previously reported procedures. Enzyme purified by the method of Heller, R. and Shrewsbury, M. (1976) J. Biol. Chem. 251, 3815-3822) shows up to 3-fold enhancement of activity by various types of lipid dispersions while the enzyme purified by the procedure of Tormanen et al. ((1976) Biochem. Biophys. Res. Commun. 68, 754-762) shows no activation. These results suggest that interaction with microsomal membrane lipids may be important in determining the activity of this enzyme. Analysis of bound lipid showed that enzyme prepared by the procedure of Tormanen contained at last 50 times as much phospholipid on a weight basis as enzyme prepared by Heller and Shrewsbury. Analysis of both preparations by gel-electrophoresis indicates that enzyme activities of the two comigrate, but in neither case does activity coincide with the major protein species.

    View details for Web of Science ID A1977DQ37700012

    View details for PubMedID 889851

  • PREVENTION OF COLD INACTIVATION OF 3-HYDROXY-3-METHYLGLUTARYL COENZYME A REDUCTASE BY NADPH BIOCHIMICA ET BIOPHYSICA ACTA Heller, R. A., Gould, R. G. 1975; 388 (2): 254-259

    Abstract

    Solubilized 3-hydroxy-3-methylglutaryl coenzyme A reductase (EC 1.1.1.34) from rat liver microsomes has been reported to be reversibly inactivated by temperatures below 19 degrees C. Cold inactivation has now been found to be completely prevented by NADPH and by NADP+ at a concentration of 3 mM. NADPH, however, was more active than NADP+ at lower concentrations and prevented 50% of the cold inactivation at 0.2 mM, whereas a 1.1 mM NADPH+ without effect and the substrate 3-hydroxy-3-methylglutaryl coenzyme A prevented only 30% of the cold inactivation at a concentration 50 times greater than the Km value.

    View details for Web of Science ID A1975AD43800011

    View details for PubMedID 237546

  • REVERSIBLE COLD INACTIVATION OF MICROSOMAL 3-HYDROXY-3-METHYLGLUTARYL COENZYME-A REDUCTASE FROM RAT-LIVER JOURNAL OF BIOLOGICAL CHEMISTRY Heller, R. A., Gould, R. G. 1974; 249 (16): 5254-5260

    View details for Web of Science ID A1974T988400036

    View details for PubMedID 4854147

  • SOLUBILIZATION AND PARTIAL-PURIFICATION OF HEPATIC 3-HYDROXY-3-METHYLGLUTARYL COENZYME A REDUCTASE BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS Heller, R. A., Gould, R. G. 1973; 50 (3): 859-865

    View details for Web of Science ID A1973O703800039

    View details for PubMedID 4689083