Kenneth L. Tyler, M.D.
Title(s): Professor
Rueler-Lewin Family Professor
Department of Neurology UCHSC
Departments of Microbiology, Immunology, and Medicine
Education:
Harvard University,A.B. (1974)
The Johns Hopkins University School of Medicine, M.D. (1978)
Email: ken.tyler@uchsc.edu
Website: http://www.uchsc.edu/sm/neuro/tylerlab/
Telephone: 303-393-4684
Fax: 303-393-4686
 
 

Clinical Practice:

Dr. Tyler sub-specializes in CNS infections. He sees patients at the Veterans Affairs Medical Center.

Research Interests:

The laboratory uses both in vivo and vitro models to study the molecular andgenetic basis of viral pathogenesis and viral-induced cell death. A major research effort investigates the mechanisms by which viruses induce apoptosis. Currentprojects include: (1) investigating the role played by specific viral genes and the proteins they encode in triggering apoptosis; (2) identifying the role of apoptosis in mediating virus-induced tissue injury in various target organs, including the CNS, in vivo, (3) defining the cellular pathways by which apoptosis is induced in virus-infected cells. Studies of cellular mechanisms of apoptosis currently involve investigations into virus-induced alterations in MAP kinase and other signal transduction pathways, transcriptional activators including c-Jun and NF-kB, the use of genomic microarray and proteomic technology to identify genes and proteins altered during viral infection of target cells, and identifying death-receptor and mitochondrial caspase signaling pathways. Further details about specific personnel and their projects can be found on the Tyler laboratory web site at: http://www.uchsc.edu/sm/neuro/tylerlab.

Ongoing IRB-approved clinical research studies:

  • Projects sponsored by the Collaborative Antiviral Study Group (CASG)(CASG 204: Double-blind placebo controlled trial of long-term therapy of HSV encephalitis with valacyclovir)
  • The AIDS Clinical Trials Group (ACTG)(ACTG A5090: A Phase II placebo-controlled double blind study of selegeline in the treatment of HIV-dementia)
  • The Neurologic AIDS Research Consortium (NARC)(NARC 007: Clinical Validation of the AACTG NeuroScreen Test).

Effective host immune defense depends on the coordinated response of both innate and adaptive arms of the immune system and the directed migration of leukocytes to chemoattractants is an integral component of both responses. Chemokine and lysophospholipid chemoattractants signal via their respective chemoattractant G-protein coupled receptors (GPCRs) expressed by hematopoietic cells and result in the spatially-restricted activation of Rho family GTPases. For relatively motile leukocytes, however, regulated cell movement further requires the coordinate release of the cell trailing edge from integrin-mediated adhesive interactions. The overall focus of our laboratory investigates how lymphocytes and cells of the innate immune system regulate chemotaxis and adhesion during homeostatic and inflammatory conditions. To address these issues, we employ complementary systems that rely on molecular, cellular, and genetic approaches coupled to in vivo and in vitro analyses of leukocyte migration and adhesion.

BCR regulation of migration and adhesion in B cell development and function
Immature B cells develop in the adult bone marrow within a microenviroment that includes contact with stromal cells expressing cytokines, chemokines and adhesion molecules that promote appropriate maturation. As soon as immature B cells express a B cell antigen receptor (BCR) on the surface it is tested for self-reactivity and immature B cells harboring a non-autoreactive antigen receptor emigrate to the periphery whereas autoreactive immature B cells are retained in the bone marrow and rendered tolerant. As a mature B lymphocyte in peripheral tissues, encounter with foreign antigen leads to an antibody response that facilitates the neutralization and clearance of the potential pathogen. BCR signaling by mature B lymphocytes differs in significant ways compared with bone marrow immature B cells. Yet, similar to immature B cells, BCR signaling by mature B cells also influences the subsequent trafficking of the activated cell through alterations in chemoattractant responsiveness and integrin adhesion. This regulation of chemoattractant migration after antigen recognition plays an important in vivo role during an immune response by directing antigen-activated B lymphocytes to microenvironments that induce appropriate antibody production. Thus, a common feature of antigen receptor signaling exhibited by both immature and mature B cells is the subsequent directed migration of the cell for appropriate further differentiation. Work in our lab uses in vivo and in vitro approaches to investigate how BCR signaling influences both chemoattractant responsiveness and integrin adhesion to accomplish these events within these distinct B cell developmental stages.

Regulation of leukocyte migration and adhesion in lung immunity
Leukocytes are resident in the lungs of healthy individuals and are necessary for orchestrating the innate and adaptive immune response towards the antigenic challenges that are inspired on a constant basis. However, inappropriate regulation of lung immunity can also lead to chronic inflammation and subsequent tissue damage and pathophysiology, hallmarks of both asthma and chronic obstructive pulmonary disease. An additional area of investigation in our lab examines how leukocytes regulate chemoattractant responsiveness and cell adhesion during inflammation in the lung and how aberrant regulation of these processes may facilitate these inflammatory lung diseases.

Selected Publications:

  • Clarke P, Meintzer SM, Moffitt L, Tyler KL. Two distinct phases of virus-induced NF-kappaB- regulation enhance TRAIL-mediated apoptosis in virus-infected cells. J Biol Chem. 2003 Mar 13.
  • Richardson-Burns SM, Kleinschmidt-DeMasters BK, DeBiasi RL, Tyler KL. Progressive multifocal leukoencephalopathy and apoptosis of infected oligodendrocytes in the central nervous system of patients with and without AIDS. Arch Neurol. 2002 Dec;59(12):1930-6.
  • DeBiasi RL, Kleinschmidt-DeMasters BK, Richardson-Burns S, Tyler KL. Central nervous system apoptosis in human herpes simplex virus and cytomegalovirus encephalitis.
    J Infect Dis. 2002 Dec 1;186(11):1547-57.
  • Kominsky DJ, Bickel RJ, Tyler KL. Reovirus-induced apoptosis requires mitochondrial release of Smac/DIABLO and involves reduction of cellular inhibitor of apoptosis protein levels.
    J Virol. 2002 Nov;76(22):11414-24.
  • Richardson-Burns SM, Kominsky DJ, Tyler KL. Reovirus-induced neuronal apoptosis is mediated by caspase 3 and is associated with the activation of death receptors. J Neurovirol. 2002 Oct;8(5):365-80.
  • Kominsky DJ, Bickel RJ, Tyler KL. Reovirus-induced apoptosis requires both death receptor- and mitochondrial-mediated caspase-dependent pathways of cell death. Cell Death Differ. 2002 Sep;9(9):926-33.
  • Poggioli GJ, DeBiasi RL, Bickel R, Jotte R, Spalding A, Johnson GL, Tyler KL. Reovirus-induced alterations in gene expression related to cell cycle regulation. J Virol. 2002 Mar;76(6):2585-94.
  • Spalding AC, Jotte RM, Scheinman RI, Geraci MW, Clarke P, Tyler KL, Johnson GL. TRAIL and inhibitors of apoptosis are opposing determinants for NF-kappaB-dependent, genotoxin-induced apoptosis of cancer cells. Oncogene. 2002 Jan 10;21(2):260-71.
  • Clarke P, Meintzer SM, Widmann C, Johnson GL, Tyler KL. Reovirus infection activates JNK and the JNK-dependent transcription factor c-Jun. J Virol. 2001 Dec;75(23):11275-83.
  • Tyler KL, Clarke P, DeBiasi RL, Kominsky D, Poggioli GJ. Reoviruses and the host cell.
    Trends Microbiol. 2001 Nov;9(11):560-4. Review.
  • Clarke P, Meintzer SM, Spalding AC, Johnson GL, Tyler KL. Caspase 8-dependent sensitization of cancer cells to TRAIL-induced apoptosis following reovirus-infection. Oncogene. 2001 Oct 18;20(47):6910-9.
  • Poggioli GJ, Dermody TS, Tyler KL. Reovirus-induced sigma1s-dependent G(2)/M phase cell cycle arrest is associated with inhibition of p34(cdc2). J Virol. 2001 Aug;75(16):7429-34.
  • DeBiasi RL, Edelstein CL, Sherry B, Tyler KL. Calpain inhibition protects against virus-induced apoptotic myocardial injury. J Virol. 2001 Jan;75(1):351-61.
  • Poggioli GJ, Keefer C, Connolly JL, Dermody TS, Tyler KL. Reovirus-induced G(2)/M cell cycle arrest requires sigma1s and occurs in the absence of apoptosis. J Virol. 2000 Oct;74(20):9562-70.
  • Clarke P, Meintzer SM, Gibson S, Widmann C, Garrington TP, Johnson GL, Tyler KL. Reovirus-induced apoptosis is mediated by TRAIL. J Virol. 2000 Sep;74(17):8135-9.
  • Yujiri T, Ware M, Widmann C, Oyer R, Russell D, Chan E, Zaitsu Y, Clarke P, Tyler K, Oka Y, Fanger GR, Henson P, Johnson GL. MEK kinase 1 gene disruption alters cell migration and c-Jun NH2-terminal kinase regulation but does not cause a measurable defect in NF-kappa B activation. Proc Natl Acad Sci U S A. 2000 Jun 20;97(13):7272-7.
  • Connolly JL, Rodgers SE, Clarke P, Ballard DW, Kerr LD, Tyler KL, Dermody TS. Reovirus-induced apoptosis requires activation of transcription factor NF-kappaB. J Virol. 2000 Apr;74(7):2981-9.
  • Debiasi RL, Squier MK, Pike B, Wynes M, Dermody TS, Cohen JJ, Tyler KL. Reovirus-induced apoptosis is preceded by increased cellular calpain activity and is blocked by calpain inhibitors. J Virol. 1999 Jan;73(1):695-701.
  • Tyler KL. Pathogenesis of reovirus infections of the central nervous system. Curr Top Microbiol Immunol. 1998;233 Reovir.ii:93-124. Review. No abstract available.
  • Oberhaus SM, Dermody TS, Tyler KL. Apoptosis and the cytopathic effects of reovirus.
    Curr Top Microbiol Immunol. 1998;233 Reovir.ii:23-49. Review. No abstract available.
  • Oberhaus SM, Smith RL, Clayton GH, Dermody TS, Tyler KL.
    Reovirus infection and tissue injury in the mouse central nervous system are associated with apoptosis. J Virol. 1997 Mar;71(3):2100-6.
  • Rodgers SE, Barton ES, Oberhaus SM, Pike B, Gibson CA, Tyler KL, Dermody TS. Reovirus-induced apoptosis of MDCK cells is not linked to viral yield and is blocked by Bcl-2. J Virol. 1997 Mar;71(3):2540-6.
  • Tyler KL, Squier MK, Brown AL, Pike B, Willis D, Oberhaus SM, Dermody TS, Cohen JJ. Linkage between reovirus-induced apoptosis and inhibition of cellular DNA synthesis: role of the S1 and M2 genes. J Virol. 1996 Nov;70(11):7984-91.
  • Tyler KL, Squier MK, Rodgers SE, Schneider BE, Oberhaus SM, Grdina TA, Cohen JJ, Dermody TS. Differences in the capacity of reovirus strains to induce apoptosis are determined by the viral attachment protein sigma 1. J Virol. 1995 Nov;69(11):6972-9.
  • Virgin HW 4th, Tyler KL. Role of immune cells in protection against and control of reovirus infection in neonatal mice. J Virol. 1991 Oct;65(10):5157-64. PMID: 1654436 [PubMed - indexed for MEDLINE]
  • Tyler KL, Virgin HW 4th, Bassel-Duby R, Fields BN. Antibody inhibits defined stages in the pathogenesis of reovirus serotype 3 infection of the central nervous system. J Exp Med. 1989 Sep 1;170(3):887-900.
  • Virgin HW 4th, Bassel-Duby R, Fields BN, Tyler KL. Antibody protects against lethal infection with the neurally spreading reovirus type 3 (Dearing). J Virol. 1988 Dec;62(12):4594-604.
  • Bassel-Duby R, Spriggs DR, Tyler KL, Fields BN. Identification of attenuating mutations on the reovirus type 3 S1 double-stranded RNA segment with a rapid sequencing technique. J Virol. 1986 Oct;60(1):64-7.
  • Tyler KL, McPhee DA, Fields BN. Distinct pathways of viral spread in the host determined by reovirus S1 gene segment. Science. 1986 Aug 15;233(4765):770-4.
  • Kaye KM, Spriggs DR, Bassel-Duby R, Fields BN, Tyler KL. Genetic basis for altered pathogenesis of an immune-selected antigenic variant of reovirus type 3 (Dearing). J Virol. 1986 Jul;59(1):90-7.

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