Horst R. Zielke
|Administrative Title: Division Head, Pediatric Research
Ron Zielke received his B.S. from the University of Illinois with a major in chemistry. He received a Ph.D. in biochemistry in 1968 from Michigan State University. His Ph.D. thesis involved studies on the incorporation of several radioactive precursors, including 14CO2, into nicotine using whole tobacco plants. Each carbon was chemically isolated for quantitation. Subsequently, he did a postdoctoral fellowship at the Atomic Energy Commission Plant Research laboratory on the campus of Michigan State University in which he studied enzyme induction using heavy isotopes. In 1971 he accepted a postdoctoral position with John Littlefield in the Genetics Unit of the Massachusetts General Hospital in Boston. The research focused on enzyme changes during the cell cycle of cultured human lymphoblasts. In 1973 he accepted a position as Assistant Professor in the Department of Pediatrics at the University of Maryland School of Medicine.
The primary focus of the research in my laboratory is on energy metabolism in mammalian cells, particularly in the brain. Early research demonstrated that human diploid fibroblasts are capable of utilizing glutamine as their sole energy source if critical anabolic functions of glucose were replaced by the addition of nucleosides. This work was extended to the developing rodent brain, both in vitro and in vivo. In vitro studies were performed with primary astrocyte and neuronal cultures. In vivo studies relied on the unique development of microdialysis techniques in which 14C-labelled compounds, that were potential energy substrate in the brain, were diffused into the brain and 14CO2 produced at the infusion site was measured using the same microdialysis probe. These studies demonstrated that although the rodent brain was able to oxidize multiple energy sources, neurons preferentially utilized glucose. Similar studies were performed in a rat pup hypoxia/ischemia model to better understand energy metabolism in the damaged pup brain.
Transport and metabolism of branched chain amino acids were studied by microdialysis in a rodent model for Maple Syrup Disease.
Additional studies focused on multiple metabolic aspects of sudden infant death syndrome (SIDS) as well as the lack of a role of fetal hemoglobin in SIDS. Studies related to other aspects of this disorder focused on the role of the adenosine receptor levels in rodent models and in humans.
Current studies focus on the role of the enzyme glutaminase in the formation of neurotransmitter glutamate in a mouse model deficient in this enzyme.
Carol L. Zielke, Ph.D, assistant professor of pediatrics, took the lead in the adenosine studies and the study of glutamine metabolism in the mouse model. She was a collaborator in most of the remaining studies.
An additional focus of the laboratory since 1991 has been the Eunice Kennedy Shriver NICHD Brain and Tissue Bank for Developmental Disorders. The Bank is the primary pediatric brain bank in the United States for developmental disorders. Over 800 researchers in 20 countries rely on human tissue distributed by the Bank. Over 500 publications have been published based on the use of tissue from the Bank.
Lab Techniques and Equipment:
- Primary human diploid fibroblasts.
- Primary rodent astrocyte and neuronal cultures High performance liquid chromatography.
- Human brain and systemic tissue from over 3000 donors.
Selected Publications (out of 73)
ZIELKE, H.R., HONG, S.-C. and LITTLEFIELD, J.W.: Different timing of increases in activities of four X-chromosome linked enzymes during the cell cycle of synchronized human lymphoblasts. Exptl. Cell Res. 97:426-430, 1976.
ZIELKE, H.R., OZAND, P.T., TILDON, J.T., SEVDALIAN, D.A. and CORNBLATH, M.: Growth of human diploid fibroblasts in the absence of glucose utilization. Proc. Natl. Acad. Sci. USA, 734:110-4114., 1976.
ZIELKE, H.R., OZAND. P.T., TILDON, J.T., SEVDALIAN, D.A. and CORNBLATH, M.: Reciprocal regulation of glucose and glutamine utilization by cultured human diploid fibroblasts. J. Cell. Physiol. 95:41-48, 1978.
ZIELKE, H.R., OZAND, P.T., LUDDY, R.E., ZINKHAM, W.H., SCHWARTZ, A.D. and SEVDALIAN, D.A.: Elevation of pyrimidine enzyme activities in the RBC of patients with congenital hypoplastic anaemia and their parents. Brit. J. Haemat. 42:381-390, 1979.
ZIELKE, H.R., SUMBILLA, C.M., SEVDALIAN, D.A., HAWKINS, R.L., and OZAND. P.T.: Lactate: A major product of glutamine metabolism by human diploid fibroblasts. J. Cell. Physiol. 104:433-441, 1980.
SUMBILLA, C.M., ZIELKE, C.L., REED, W.D., OZAND, P.T. and ZIELKE, H.R.: Comparison of the oxidation of glutamine, glucose, ketone bodies, and fatty acids by human diploid fibroblasts. Biochim. Biophys. Acta 675:301-304, 1981.
ZIELKE, C.L., ZIELKE, H.R. and OZAND, P.T.: A radioisotope assay for glutaminase: The measurement of tritiated water formation from the reaction of L[2-3H]-glutamine with the L-glutaminase and glutamate oxalacetate transaminase couple. Anal. Biochem. 127:134-142, 1982.
SUMBILLA, C.M., ZIELKE, H.R., KRAUSE, B.L. and OZAND, P.T.: Activity of gluconeogenic enzymes in fibroblasts from infants dying of the Sudden Infant Death Syndrome. European J. Ped. 140:276-277, 1983.
ZIELKE, H.R., ZIELKE, C.L. and OZAND, P.T.: Glutamine: A major energy source for cultured mammalian cells. Fed. Proc. 43:121-125, 1984.
ZIELKE, C.L. and ZIELKE, H.R.: Chronic exposure to subcutaneously implanted methylxanthines: Differential elevation of A1-adenosine receptors in mouse cerebellum and cortex. Biochem. Pharmacol. 36:2533-2538, 1987.
ZIELKE, H.R., TILDON, J.T., ZIELKE, C.L., BAAB, P.J. and LANDRY, M.E.: Functional intracellular glutaminase activity in intact astrocytes. Neurochem. Res. 14(4)427-432, 1989.
ZIELKE, H.R., MENY, R.G., O'BRIEN, M.J., SMIALEK,J.E., KUTLAR, F., HUISMAN, T.H.J. and DOVER, G.J.: Normal fetal hemoglobin levels in the Sudden Infant Death Syndrome. N. Engl. J. Med. 321:1359-1364, 1989.
SHANK, R.P., LEO, G.C., and ZIELKE, H.R.: Cerebral metabolic compartmentation as revealed by nuclear magnetic resonance analysis of [1-13C]D-glucose metabolism. J. Neurochem. 61:315-323, 1993.
HUANG, Y., ZIELKE, C.L., TILDON, J.T., and ZIELKE, H.R.: Monitoring in vivo oxidation of 14C-labelled substrates to 14CO2 by brain microdialysis. Dev. Neurosci. 15:233-239, 1993.
MCKENNA, M.C,, SONNEWALD, U., HUANG, X., STEVENSON, J.H. and ZIELKE, H.R.: Exogenous glutamate concentration regulates the metabolic fate of glutamate in astrocytes. J. Neurochem. 66:386-393, 1996.
ZIELKE, H.R., WISNIEWSKI, S. and STEIN, S.A.: The Role of National Brain and Tissue Banks in Research on Autism and Developmental Disorders. J. Autism Develop. Dis. 26:227-230, 1996.
ZIELKE, H.R., TILDON, J.T., and ZIELKE, C.L.: Use of intracellular versus extracellular specific activities in calculation of glutamine metabolism in astrocytes: Effect of dibutyryl cyclic AMP. Develop. Neurosci.18:224-230, 1996.
HUANG, Y., ZIELKE, H.R., TILDON, J.T., ZIELKE, C.L., and BAAB, P.J.: Elevation of amino acids in the interstitial space of the rat brain following infusion of large neutral amino and keto acids by microdialysis: Leucine infusion. Develop. Neurosci. 18:415-419, 1996.
ZIELKE, H.R., HUANG, Y., TILDON, J.T., ZIELKE, C.L., and BAAB, P.J.: Elevation of amino acids in the interstitial space of the rat brain following infusion of large neutral amino and keto acids by microdialysis: ï¡-Ketoisocaproate infusion. Develop. Neurosc. 18:420-425, 1996.
ZIELKE, H.R., COLLINS, R.M. Jr., BAAB, P.J., HUANG, Y., ZIELKE, C.L. and TILDON, J.T.: Compartmentation of [14C]-glutamate and [14C]-glutamine oxidative metabolism in the rat brain. J. Neurochem. 71:1315-1320, 1998.
HODGKINS, P.S., WU, H.-Q., ZIELKE, H.R. and SCHWARCZ, R.: 2-Oxoacids regulate kynurenic acid production in the rat brain: Studies in vitro and in vivo. J. Neurochem. 72:643-651, 1999.
LU, R., WANG, W., UZZAU, S., VIGORITO, R.D., ZIELKE, H.R. and FASANO, A.: Affinity purification and partial characterization of the zonulin/zonula occudens toxin (Zot) receptor from human brain. J. Neurochem. 74:320-326, 2000.
MATTHEWS, C.C., ZIELKE, H.R., WOLLACK, J.B. and FISHMAN, P.S.: Enzymatic degradation protects neurons from glutamate toxicity. J. Neurochem. 75:1045-1052, 2000.
ZIELKE, H.R., ZIELKE, C.L., BAAB, P.J. and COLLINS, R.M.: Large neutral amino acids auto exchange when infused by microdialysis into the rat brain: implication for maple syrup urine disease and phenylketonuria. Neurochem Intrn. 40:347-354, 2002.
MENY, R.G., VREMAN, H.., STEVENSON, D.K., HAUCK, F.R., DONOGHUE, E.R., SMIALEK, FOWLER, D.R. and ZIELKE, H.R.: Failure to detect elevated levels of carboxyhemoglobin in infants dying from SIDS. J. Forensic Sci. 47:660-662, 2002.
KISS, C., CERESOLI-BORRONI, G., GUIDETTI, P., ZIELKE, C.L., ZIELKE, H.R. and SCHWARCZ, R.: Kynurenate production by cultured human astrocytes. J. Neurol Transm., 110:1-14, 2003.
JONES, J.L., KROUS, H.F., NADEAU, J., BLACKBOURNE, B., ZIELKE, H.R. and GOZAL, D.: Vascular endothelial growth factor in the cerebrospinal fluid of infants who died of Sudden Infant Death Syndrome: evidence for antecedent hypoxia. Pediatrics, 111:358-363, 2003.
MATTHEWS, C.C., ZIELKE, H.R., and FISHMAN, P.S.: Glutamate-pyruvate transaminase protects against glutamate toxicity in hippocampal slices. Brain Research, 978:59-64, 2003.
MAO, RONG, ZIELKE, C.L., ZIELKE, H.R. and PEVSNER, J.: Global up-regulation of chromosome 21 gene expression in the developing Down Syndrome brain. Genomics, 81:457-467, 2003.
TCHAKMAKJIAN, L., GARDNER, J.P., WILSON, P.D., KIMURA, M., SHURNICK, J., ZIELKE, H.R., and AVIV, A.: Age-dependent telomere attrition as an indicator of racial differences in renal growth patterns. Nephron Exp. Nephrol. 98:e82-e88, 2004.
HERTZ, L. and ZIELKE, H.R. Astrocytic control of glutamatergic activity: astrocytes as stars of the show. TRENDS in Neuroscience 27:735-743, 2004.
TIAN, G.F., AZMI, T., TAKANO, T., XU, Q., PENG, W., LIN, J., OBERHEIM, N.A., LOU, N., WANG, X., ZIELKE, H.R., KANG, J. and NEDERGAARD, M.: An astrocytic basis of epilepsy. Nature, Med. 11:973-981, 2005.
WATTS, T., BERTI, I., SAPONE, A., GERARDUZZI, T., NOTE, T., ZIELKE, R. and FASANO, A. Role of the intestinal tight junction modulator zonulin in the pathogenesis of type I diabetes in BB diabetic-prone rats. Proc. Natl. Acad. Sci. (U.S.A.) 102:2916-2921, 2005.
CRUZ, N.F., LASATER, A., ZIELKE, H.R. and DIENEL, G.A. Activation of astrocytes in brain of conscious rats during acoustic stimulation: acetate utilization in working brain. J. Neurochem. 92: 934-947, 2005.
TAKANO, T., ARACUINO, G., LIN, J.H.-C., KANG, J., YU, Y., LIU, Q.-S., DIENEL, G., ZIELKE, H.R. and NEDERGAARD, M.: Receptor-mediated glutamate release from volume sensitive channels in astrocytes. Proc. Natl. Acad. Sci. (U.S.A.)102(45):16466-16471, 2005.
VREMAN, H.J., WONG, R.J., STEVENSON, D.K., SMIALEK, J.E., FOWLER, D.R., LI, L., VIROGITO, R.D. and ZIELKE, H.R. Concentration of carbon monoxide (CO) in postmortem human tissues: effects of environmental CO exposure. J. Forensic Sci. 51(5):1182-1190, 2006.
ZIELKE, H.R., ZIELKE, C.L., BAAB, P.J., and TILDON, J.T. Effect of fluorocitrate on cerebral oxidation of lactate and glucose in freely moving rats. J. Neurochem. 101:9-16, 2007.
ZIELKE, H.R., ZIELKE, C.L., and BAAB, P.J. Oxidation of 14C-labeled compounds perfused by microdialysis into the brain of free moving rats. J. Neurosci. Res. 85:3145-3149, 2007.
ZIELKE, H.R., ZIELKE, C.L., and BAAB, P.J. Direct measurement of oxidative metabolism in the living brain by microdialysis. J. Neurochem. 109(Suppl. 1):24-29, 2009.
BLUTSTEIN, T., BAAB, P.J., ZIELKE, H.R. and MONG,J.A. Hormonal modulation of amino acid metabolism in the arculate nucleus of the adult female rate: A novel action of estradiol. Endocrinology 150(7):3237-3244, 2009.
ALMEIDA, L.E.F., MURRAY, P.D., ZIELKE, H.R., ROBY, C.D., KINGSBURY, T.J. and KRUEGER, B.K. Autocrine activation of neuronal NMDA receptors by aspartate mediates dopamine- and cAMP-induced CREB-dependent gene transcription. J. Neurosci. 29(40):12702-12710, 2009.
LI, L., ZHANG, Y., ZIELKE, H.R., and FOWLER, D.R. Observations on increased accidental asphyxia deaths in infancy while co-sleeping in the state of Maryland. Amer. J. For. Med. Path. 30(4) 318-321, 2009.
GIBBS, J.R., VAN DER BRUG, M.P., HERNANDEZ, D.G., TRAYNOR, B.J., NALLS, M.A., LAI, S.-L., AREPALLI, S., DILLMAN, A., RAFFERTY, I.P., TRONCOSO, J. JOHNSON, R., ZIELKE, H.R., FERRUCCI, L., LONGO, D.L., COOKSON, M.R. and SINGLETON, A.B. Abundant quantitative trait loci exist for DNA methylation and gene expression in human brain. PLOS Genetics, 2010, 6(5): e1000952. doi:10.1371/journal.pgen.1000952