David S. Middlemas, PhD



Work: 660.626.2326
Fax: 660.626.2728
Email Address: dmiddlemas@atsu.edu

Research Interests: Dr. Middlemas is interested in the role brain-derived neutrophic factor (BDNF) has in the mechanism of drug action. BDNF activates cellular signaling pathways via its receptor, the protein tyrosine kinase, TrkB. Of particular interest, BDNF may be required for antidepressant drug action. Dr. Middlemas is interested in whether there are differences in the mechanism of action of antidepressant drugs in children and adults. The developing nervous system of juveniles may respond differently to these drugs than the adult nervous system. Using a juvenile rat model, the laboratory is investigating whether antidepressant drugs induce neurogenesis and whether brain-derived neurotrophic factor (BDNF) is required for antidepressant drug action. These studies also focus on the role of specific BDNF signaling pathways previously identified by the laboratory in antidepressant drug action. The goal is to increase our understanding of antidepressant drug action in the developing nervous system and identify targets for antidepressant drug discovery in juveniles.

Education:

PhD - California Institute of Technology (1987)

Scholarly Activity

Research Publications:

2008 | Kozisek ME, Middlemas DS, Bylund DB. The differential regulation of BDNF and TrkB levels in juvenile rats after four days of escitalopram and desipramine treatment. Neuropharmacology. 2008 Feb;54(2):251-7

2008 | Kozisek ME, Middlemas DS, Bylund DB. Brain-derived neurotrophic factor and its receptor tropomyosin-related kinase B in the mechanism of action of antidepressant therapies. Pharmacol Ther. 2008 Jan;117(1):30-51

2006 | Easton JB, Royer AR, Middlemas DS. 2006. The protein tyrosine phosphatase, Shp2, is required for the complete activation of the RAS/MAPK pathway by brain-derived neurotrophic factor. J Neurochem. 2006 May;97(3):834-45

2000 | Middlemas DS, Stewart CF, Kirstein MN, Poquette C, Friedman HS, Houghton PJ, Brent TP. Biochemical correlates of temozolomide sensitivity in pediatric solid tumor xenograft models. Clin Cancer Res. 2000 Mar;6(3):998-1007

1999 | Middlemas DS, Kihl BK, Moody NM. Brain derived neurotrophic factor protects human neuroblastoma cells from DNA damaging agents. J Neurooncol. 1999;45(1):27-36

1999 | McKenzie PP, Guichard SM, Middlemas DS, Ashmun RA, Danks MK, Harris LC. Wild-type p53 can induce p21 and apoptosis in neuroblastoma cells but the DNA damage-induced G1 checkpoint function is attenuated. Clin Cancer Res. 1999 Dec;5(12):4199-207

1999 | Middlemas DS, Kihl BK, Zhou J, Zhu X. Brain-derived neurotrophic factor promotes survival and chemoprotection of human neuroblastoma cells. J Biol Chem. 1999 Jun 4;274(23):16451-60

1999 | Easton JB, Moody NM, Zhu X, Middlemas DS. Brain-derived neurotrophic factor induces phosphorylation of fibroblast growth factor receptor substrate 2. J Biol Chem. 1999 Apr 16;274(16):11321-7

1998 | Srinivas RV, Middlemas D, Flynn P, Fridland A. Human immunodeficiency virus protease inhibitors serve as substrates for multidrug transporter proteins MDR1 and MRP1 but retain antiviral efficacy in cell lines expressing these transporters. Antimicrob Agents Chemother. 1998 Dec;42(12):3157-62

1994 | Middlemas DS, Meisenhelder J, Hunter T. Identification of TrkB autophosphorylation sites and evidence that phospholipase C-gamma 1 is a substrate of the TrkB receptor. J Biol Chem. 1994 Feb 18;269(7):5458-66

1993 | Merlio JP, Ernfors P, Kokaia Z, Middlemas DS, Bengzon J, Kokaia M, Smith ML, Siesjo BK, Hunter T, Lindvall O, et al. Increased production of the TrkB protein tyrosine kinase receptor after brain insults. Neuron. 1993 Feb;10(2):151-64

1992 | Frisen J, Verge VM, Cullheim S, Persson H, Fried K, Middlemas DS, Hunter T, Hokfelt T, Risling M. Increased levels of trkB mRNA and trkB protein-like immunoreactivity in the injured rat and cat spinal cord. Proc Natl Acad Sci U S A. 1992 Dec 1;89(23):11282-6

1991 | Soppet D, Escandon E, Maragos J, Middlemas DS, Reid SW, Blair J, Burton LE, Stanton BR, Kaplan DR, Hunter T, et al. The neurotrophic factors brain-derived neurotrophic factor and neurotrophin-3 are ligands for the trkB tyrosine kinase receptor. Cell. 1991 May 31;65(5):895-903

1991 | Middlemas DS, Lindberg RA, Hunter T. trkB, a neural receptor protein-tyrosine kinase: evidence for a full-length and two truncated receptors. Mol Cell Biol. 1991 Jan;11(1):143-53

1988 | Weinmaster GA, Middlemas DS, Hunter T. A major site of tyrosine phosphorylation within the SH2 domain of Fujinami sarcoma virus P130gag-fps is not required for protein-tyrosine kinase activity or transforming potential. J Virol. 1988 Jun;62(6):2016-25

1987 | Middlemas DS, Raftery MA. Identification of subunits of acetylcholine receptor that interact with a cholesterol photoaffinity probe. Biochemistry. 1987 Mar 10;26(5):1219-23

1985 | Olivera BM, McIntosh JM, Clark C, Middlemas D, Gray WR, Cruz LJ. A sleep-inducing peptide from Conus geographus venom. Toxicon. 1985;23(2):277-82

1983 | Middlemas DS, Raftery MA. Exposure of acetylcholine receptor to the lipid bilayer. Biochem Biophys Res Commun. 1983 Sep 30;115(3):1075-82

Books, Chapters, and Reviews:

2000 | Middlemas DS and Houghton PJ. 2000. Preclinical models for neuroblastoma therapy. Neuroblastoma (Brodeur GM, Sawada T, Tsuchiada Y, Voute PA, Eds.) Elsevier Science, Amsterdam, pp. 393-402

1993 | Middlemas DS. 1993. Receptor protein-tyrosine kinases. Methods in Neurosciences (Conn PM, Ed.), Academic Press, New York Vol,12, 139-155

1992 | Hunter T, Lindberg RA, Middlemas DS, Tracy S, van der Geer P. Receptor protein tyrosine kinases and phosphatases. Cold Spring Harb Symp Quant Biol. 1992;57:25-41. Review

1990 | Hunter T, Lindberg RA, Middlemas DS. Novel receptor protein-tyrosine kinases. Adv Second Messenger Phosphoprotein Res. 1990;24:260-5

1989 | Hunter T, Gould KL, Lindberg RA, Meisenhelder J, Middlemas DS, Thompson DP. 1989. Protein-tyrosine kinases and their substrates: old friends and new faces. Protein Design and the Development of New Therapeutics and Vaccine. (Poste G, Crooke ST, Eds.) Plenum Publishing Corp, New York, pp. 119-139

1986 | Middlemas DS, Zabrecky JR, Raftery MA. 1986. Cholesterol interaction with and influence on the function of the nicotinic acetylcholine receptor. Molecular Architecture of Proteins and Enzymes (Bradshaw RA, Tang J, Eds.) Academic Press, New York, pp. 195-208

1985 | Gray WR, Middlemas DS, Zeikus R, Olivera BM, Cruz L. 1985. Structure-activity relationships in α-conotoxins: a model. Peptides: Structure and Function (Deber CM, Hruby VJ, Kopple KD, Eds.) Pierce Chemical Company, pp. 823-832.

1985 | Raftery MA, Conti-Tronconi BM, Dunn SMJ, Crawford RD, Middlemas DS. 1985. Concepts of cholinergic receptor function. Mechanisms of Receptor Regulation, (Poste G, Crooke ST, Eds.) Plenum Publishing Corporation, pp. 255-278.

1984 | Raftery MA, Conti-Tronconi BM, Dunn SM, Crawford RD, Middlemas D. The nicotinic acetylcholine receptor: its structure, multiple binding sites, and cation transport properties. Fundam Appl Toxicol. 1984 Apr;4(2 Pt 2):S34-51

1983 | Raftery MA, Dunn SM, Conti-Tronconi BM, Middlemas DS, Crawford RD. The nicotinic acetylcholine receptor: subunit structure, functional binding sites, and ion transport properties. Cold Spring Harb Symp Quant Biol. 1983;48 Pt 1:21-33

Presentations and Published Abstracts:

2016 | Jackson TM, Stanley EM, Ostrowski TD, Middlemas DS. Does Ghrelin Effectively Reduce Depressive-like Symptoms in Juvenile Rats? Poster presented at the 8th Annual Interdisciplinary Biomedical Research Conference; Kirksville, MO; November 5, 2016. Nickle TR [student], Stanley EM, Meyer TJ, Middlemas DS. Corticosterone induces depressive-like behavior in female peri-pubescent rats, but not pre-pubescent rats. Poster presented at the 7th Annual Interdisciplinary Biomedical Research Conference; Kirksville, MO; October 31, 2015.

2015 | Stanley EM, Cho A, Middlemas DS. Is Olanzapine Predicted to have Antidepressant Effects on Juvenile Rats in the Forced Swim Test? Poster presented at the 7th Annual Interdisciplinary Biomedical Research Conference; Kirksville, MO; October 31, 2015.

2014 | Stanley EM, Middlemas DS, Smith S, Hovorka M, Ewing D. Effects of 8-OH-DPAT and Olanzapine on Adolescent Rats. Poster presented at 6th Annual Interdisciplinary Biomedical Research Conference; Kirksville, MO; November 1, 2014.

2013 | Nickle TR [student], Middlemas DS. The Effect of Chronic Corticosterone-Induced Treatment in Pre- and Post-Pubescent Female Rats, Poster presented at 5th Annual Interdisciplinary Biomedical Research Conference; Kirksville, MO; November 2, 2013.

2013 | Young M [student], Middlemas D. Does Agomelatine Have Antidepressant Action? Poster presented at 5th Annual Interdisciplinary Biomedical Research Conference; Kirksville, MO; November 2, 2013.

2011 | Smith S [staff], Hovorka M[staff], Middlemas DS. Chronic Buspirone Treatment Increases Newborn Cell Survival in the Dentate Gyrus of the Hippocampus in an Adolescent Rat Model. Poster presented at 3rd Annual Interdisciplinary Biomedical Research Conference; Kirksville, MO; October 22, 2011.

2010 | Bubel J [student], Hovorka M [staff], Middlemas D. Changes in Brain Derived Neurotrophic Factor Levels during Antidepressant Drug-enhanced Neurogenesis. Poster presented at 2nd Annual Interdisciplinary Biomedical Research Conference; Kirksville, MO; October 9, 2010.

2010 | Hovorka M [staff], Bubel J [student], Middlemas D. Chronic Fluoxetine Treatment Increases Neurogenesis in an Adolescent Rat Model. Poster presented at 2nd Annual Interdisciplinary Biomedical Research Conference; Kirksville, MO; October 9, 2010.

2009 | Bubel J [student], Hovorka MS [staff], Middlemas DS; Expression of TrkB in neuronal maturation in newborn cells and more mature neurons; Presented at the 1st Annual Interdisciplinary Biomedical Research Symposium; A.T. Still University of Health Sciences; Kirksville, MO; Sept. 26, 2009.

2009 | Ewing D, Hovorka MS [staff], Klatt E [student], Piel E, Middlemas DS; The effect of chronic antidepressant treatment on neurogenesis in a juvenile rat model; Presented at the 1st Annual Interdisciplinary Biomedical Research Symposium; A.T. Still University of Health Sciences; Kirksville, MO; Sept. 26, 2009.