Training in Molecular and Mechanistic Toxicology

Summary

Principal Investigator: Edson X Albuquerque
Abstract: DESCRIPTION (provide by applicant) This application is for continuation of a toxicology training program at University of Maryland (UM). The objective is to train graduate students and postdoctoral fellows in neurotoxicology, cell injury and carcinogenesis, molecular epidemiology and aquatic toxicology, with special emphasis on mechanisms and application of cutting-edge technologies to toxicological research. This proposal brings together a cadre of well funded, highly productive faculty mentors from different sites within the UM System, including the School of Medicine (SOM) and the Chesapeake Biological Laboratory. Mentors form a cohesive program designed to prepare trainees for research careers in toxicology and environmental health sciences. One of the major strengths is the exposure of the students to translational aspects of basic research in toxicology. Chemical risk assessments and the development of countermeasures to treat and/or prevent disease states induced by toxicants depends on the determination of the mechanisms by which such toxicants act, on the identification of targets for therapeutic intervention, and on the characterization of new assays, models, tools, and technologies for toxicity testing. Thus, mentors have been selected for their common interest in basic, clinical and ecological research applied to such environmental toxicants as metals, phytoestrogens, dioxins, and insecticides, and interests span from basic to clinical and environmental research. This selection provides trainees with a unique opportunity to gain experience in fields that play a major role in determining the mechanism of action and the effects of environmental toxicants in susceptible subsets of the population, including sensitive stages of development. The graduate training in toxicology combines resources of the UM system-wide Program in Toxicology and the SOM Pharmacology and Experimental Therapeutics Departmrnt (toxicology track), and includes didactic course work, laboratory rotations, seminars, research and participation in national meetings. The postdoctoral program includes training in state-of-the-art toxicology research, teaching experience, and participation in seminars and national meetings. The breadth of the program is sufficient to allow emphasis in four primary areas: The Neurotoxicology Track provides training in molecular mechanisms of neurodegeneration due to environmental toxicants and the development of chemo- and gene therapy modalities. The Cell Injury and Carcinogenesis Track provides training in the action of free radicals, calcium homeostasis, mechanisms of lead and dioxin toxicities, estrogen biosynthesis and carcinogenesis. The Molecular EpidemiologyTrack provides training in identification of biomarkers of exposure and susceptibility, and in epidemiological methods for identifying associations between environmental chemical exposures and diseases. The Aquatic Toxicology Track provides training in pathobiology, immunotoxicology and molecular mechanisms of toxicity of heavy metals, dioxin and other pollutants.
Funding Period: -----------------199 - ----------------2013
more information: NIH RePORT

Top Publications

  1. pmc Intranasal administration of the growth-compromised HSV-2 vector DeltaRR prevents kainate-induced seizures and neuronal loss in rats and mice
    Jennifer M Laing
    Department of Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine, 655 W Baltimore Street, Baltimore, MD 21201 1559, USA
    Mol Ther 13:870-81. 2006
  2. ncbi Debromination of polybrominated diphenyl ether-99 (BDE-99) in carp (Cyprinus carpio) microflora and microsomes
    Rae T Benedict
    University of Maryland Center for Environmental Science, Chesapeake Biological Laboratory, P O Box 38, Solomons, MD 20688, USA
    Chemosphere 69:987-93. 2007
  3. ncbi Growth-compromised HSV-2 vector Delta RR protects from N-methyl-D-aspartate-induced neuronal degeneration through redundant activation of the MEK/ERK and PI3-K/Akt survival pathways, either one of which overrides apoptotic cascades
    Jennifer M Laing
    Department of Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine, Baltimore, Maryland 21201 1559, USA
    J Neurosci Res 86:378-91. 2008
  4. ncbi The 44-kDa Pim-1 kinase phosphorylates BCRP/ABCG2 and thereby promotes its multimerization and drug-resistant activity in human prostate cancer cells
    Yingqiu Xie
    Department of Pharmacology and Experimental Therapeutics, University of Maryland, Baltimore 21201, USA
    J Biol Chem 283:3349-56. 2008
  5. ncbi Potent anti-prostate cancer agents derived from a novel androgen receptor down-regulating agent
    Puranik Purushottamachar
    Department of Pharmacology and Experimental Therapeutics, University of Maryland, School of Medicine, 685 West Baltimore Street, Baltimore, MD 21201 1559, USA
    Bioorg Med Chem 16:3519-29. 2008
  6. pmc Heterogeneous memory T cells in antiviral immunity and immunopathology
    David Verhoeven
    Department of Surgery, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA
    Viral Immunol 21:99-113. 2008
  7. pmc Acute skin eruptions that are positive for herpes simplex virus DNA polymerase in patients with stem cell transplantation: a new manifestation within the erythema multiforme reactive dermatoses
    Joseph W Burnett
    Department of Dermatology, University of Maryland, 4401 Roland Ave, Baltimore, MD 21210, USA
    Arch Dermatol 144:902-7. 2008
  8. pmc 17alpha-Hydroxylase/17,20 lyase inhibitor VN/124-1 inhibits growth of androgen-independent prostate cancer cells via induction of the endoplasmic reticulum stress response
    Robert D Bruno
    Department of Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine, Baltimore, MD 21201 1559, USA
    Mol Cancer Ther 7:2828-36. 2008
  9. pmc Stress-induced NQO1 controls stability of C/EBPα against 20S proteasomal degradation to regulate p63 expression with implications in protection against chemical-induced skin cancer
    B A Patrick
    Department of Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine, Baltimore, MD 21201, USA
    Oncogene 31:4362-71. 2012
  10. pmc NAD(P)H:quinone oxidoreductase 1 protects bladder epithelium against painful bladder syndrome in mice
    Brad A Patrick
    Department of Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine, Baltimore, MD 21201, USA
    Free Radic Biol Med 53:1886-93. 2012

Scientific Experts

  • Christopher J Salice
  • David Verhoeven
  • Robert D Bruno
  • Vincent C O Njar
  • Jennifer M Laing
  • Puranik Purushottamachar
  • B A Patrick
  • Edson X Albuquerque
  • Chrissy Schilling
  • Laure Aurelian
  • Edna F R Pereira
  • Matthew Fosbrink
  • Lalji K Gediya
  • Tadas S Vasaitis
  • Hegang Chen
  • Yingqiu Xie
  • L Gallicchio
  • C Schilling
  • Jodi A Flaws
  • Zhiyong Guo
  • Michael D Gober
  • Roger J Mullins
  • Brad A Patrick
  • A K Jaiswal
  • A G Colunga
  • Sonia I Vlaicu
  • Elena A Alexandrova
  • Cosmin A Tegla
  • Horea Rus
  • Violeta Rus
  • Angela M H Brodie
  • L Aurelian
  • J M Laing
  • Yasco Aracava
  • Joseph W Burnett
  • Aakanksha Khandelwal
  • Erin K Golembewski
  • H Zacur
  • S R Miller
  • Patricia Langenberg
  • B Li
  • Rae T Benedict
  • Paul J Yarowsky
  • Lisa Gallicchio
  • Susan R Miller
  • J A Flaws
  • Howard Zacur
  • Kexin Xu
  • Yun Qiu
  • Scott M Thompson
  • Kimberly P Miller
  • Jacek Mamczarz
  • Rao P Gullapalli
  • Su Xu
  • Anil K Jaiswal
  • Amitava Das
  • Zeynep Ates-Alagoz
  • Abhijit M Godbole
  • X Gong
  • Vingh Nguyen
  • Petru A Mircea
  • Abulkalam Shamsuddin
  • Philippe Azimzadeh
  • Cornelia D Cudrici
  • Sonia Vlaicu
  • Cornelia Cudrici
  • Takahiro Ito
  • Kateryna Soloviova
  • Florin Niculescu
  • Xi Yang
  • Ladan Fazli
  • Juan Liu
  • Douglas E Linn
  • Tony D Gover
  • Angelika M Burger
  • Hermela Shimelis
  • Samantha Q Wales
  • Takeo Nakanishi
  • M Samir Jafri
  • Douglas D Ross
  • Angela M Brodie
  • Martin E Gleave
  • P Langenberg
  • Carys L Mitchelmore
  • D Tomic
  • Neha Maheshwari
  • Robert J Letcher
  • M D Gober
  • C C Smith
  • Heather M Stapleton

Detail Information

Publications31

  1. pmc Intranasal administration of the growth-compromised HSV-2 vector DeltaRR prevents kainate-induced seizures and neuronal loss in rats and mice
    Jennifer M Laing
    Department of Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine, 655 W Baltimore Street, Baltimore, MD 21201 1559, USA
    Mol Ther 13:870-81. 2006
    ..Intranasally delivered DeltaRR prevents kainic acid-induced seizures, neuronal loss, and inflammation, in both rats and mice. The data suggest that DeltaRR is a promising therapeutic platform for neurodegenerative diseases...
  2. ncbi Debromination of polybrominated diphenyl ether-99 (BDE-99) in carp (Cyprinus carpio) microflora and microsomes
    Rae T Benedict
    University of Maryland Center for Environmental Science, Chesapeake Biological Laboratory, P O Box 38, Solomons, MD 20688, USA
    Chemosphere 69:987-93. 2007
    ....
  3. ncbi Growth-compromised HSV-2 vector Delta RR protects from N-methyl-D-aspartate-induced neuronal degeneration through redundant activation of the MEK/ERK and PI3-K/Akt survival pathways, either one of which overrides apoptotic cascades
    Jennifer M Laing
    Department of Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine, Baltimore, Maryland 21201 1559, USA
    J Neurosci Res 86:378-91. 2008
    ..The data indicate that Delta RR-delivered ICP10PK stimulates redundant survival pathways that override proapoptotic cascades. Delta RR is a promising gene therapy platform against glutamatergic cell death...
  4. ncbi The 44-kDa Pim-1 kinase phosphorylates BCRP/ABCG2 and thereby promotes its multimerization and drug-resistant activity in human prostate cancer cells
    Yingqiu Xie
    Department of Pharmacology and Experimental Therapeutics, University of Maryland, Baltimore 21201, USA
    J Biol Chem 283:3349-56. 2008
    ..These findings may provide a potential therapeutic approach by disrupting Pim-1 signaling to reverse BCRP-mediated multidrug resistance...
  5. ncbi Potent anti-prostate cancer agents derived from a novel androgen receptor down-regulating agent
    Puranik Purushottamachar
    Department of Pharmacology and Experimental Therapeutics, University of Maryland, School of Medicine, 685 West Baltimore Street, Baltimore, MD 21201 1559, USA
    Bioorg Med Chem 16:3519-29. 2008
    ..These novel compounds are strong candidates for development for the treatment of hormone-sensitive and importantly hormone-refractory prostate cancers in humans...
  6. pmc Heterogeneous memory T cells in antiviral immunity and immunopathology
    David Verhoeven
    Department of Surgery, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA
    Viral Immunol 21:99-113. 2008
    ....
  7. pmc Acute skin eruptions that are positive for herpes simplex virus DNA polymerase in patients with stem cell transplantation: a new manifestation within the erythema multiforme reactive dermatoses
    Joseph W Burnett
    Department of Dermatology, University of Maryland, 4401 Roland Ave, Baltimore, MD 21210, USA
    Arch Dermatol 144:902-7. 2008
    ..Therefore, one of the differential diagnostic possibilities for SCTE is HSV-associated erythema multiforme (HAEM) in which HSV genetic fragments localize in stem cells that deliver them to the skin on differentiation...
  8. pmc 17alpha-Hydroxylase/17,20 lyase inhibitor VN/124-1 inhibits growth of androgen-independent prostate cancer cells via induction of the endoplasmic reticulum stress response
    Robert D Bruno
    Department of Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine, Baltimore, MD 21201 1559, USA
    Mol Cancer Ther 7:2828-36. 2008
    ..Taken together, these findings show VN/124-1 is endowed with multiple anticancer properties that may contribute to its utility as a prostate cancer therapeutic...
  9. pmc Stress-induced NQO1 controls stability of C/EBPα against 20S proteasomal degradation to regulate p63 expression with implications in protection against chemical-induced skin cancer
    B A Patrick
    Department of Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine, Baltimore, MD 21201, USA
    Oncogene 31:4362-71. 2012
    ..The studies are significant as 2-4% human individuals are homozygous and 23% are heterozygous for the NQO1P187S mutation and might be susceptible to stress-induced skin diseases...
  10. pmc NAD(P)H:quinone oxidoreductase 1 protects bladder epithelium against painful bladder syndrome in mice
    Brad A Patrick
    Department of Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine, Baltimore, MD 21201, USA
    Free Radic Biol Med 53:1886-93. 2012
    ..These pathophysiological changes led to the incidence of PBS in NQO1(-/-) mice. Altogether, the results demonstrate for the first time that NQO1 is an endogenous factor in protection against PBS...
  11. pmc Targeting cytochrome P450 enzymes: a new approach in anti-cancer drug development
    Robert D Bruno
    Department of Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine, Baltimore, MD 21201 1559, USA
    Bioorg Med Chem 15:5047-60. 2007
    ..This review offers the first comprehensive analysis of strategies in drug development that either inhibit or exploit CYP enzymes for the treatment of cancer...
  12. ncbi Correlates of sexual functioning among mid-life women
    L Gallicchio
    Prevention and Research Center, Weinberg Center for Women s Health and Medicine, Mercy Medical Center, Baltimore, Maryland, USA
    Climacteric 10:132-42. 2007
    ..Therefore, the purpose of this study was to examine the associations between participant characteristics and endogenous hormones with sexual functioning in mid-life women...
  13. ncbi Methoxychlor metabolites may cause ovarian toxicity through estrogen-regulated pathways
    Kimberly P Miller
    Program in Toxicology and Department of Epidemiology and Preventive Medicine, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA
    Toxicol Sci 93:180-8. 2006
    ..These data suggest that MXC metabolites inhibit follicle growth and induce atresia and that ER-regulated pathways may mediate the ovarian toxicity of MXC and its metabolites...
  14. pmc Effective countermeasure against poisoning by organophosphorus insecticides and nerve agents
    Edson X Albuquerque
    Department of Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine, 655 West Baltimore Street, Baltimore, 21201, USA
    Proc Natl Acad Sci U S A 103:13220-5. 2006
    ..Thus, a galantamine-based therapy emerges as an effective and safe countermeasure against OP poisoning...
  15. pmc Delayed hippocampal effects from a single exposure of prepubertal guinea pigs to sub-lethal dose of chlorpyrifos: a magnetic resonance imaging and spectroscopy study
    Roger J Mullins
    Department of Diagnostic Radiology and Nuclear Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, United States
    Neurotoxicology 36:42-8. 2013
    ....
  16. pmc The growth compromised HSV-2 mutant DeltaRR prevents kainic acid-induced apoptosis and loss of function in organotypic hippocampal cultures
    Michael D Gober
    Department of Pharmacology and Experimental Therapeutics, University of Maryland, School of Medicine, Baltimore, MD 21201 1559, USA
    Brain Res 1119:26-39. 2006
    ..The surviving neurons retained normal synaptic function potentially related to increased expression of the transcription factor CREB. The data indicate that DeltaRR is a promising platform for neuroprotection from excitotoxic injury...
  17. ncbi Regulation of androgen receptor activity by tyrosine phosphorylation
    Zhiyong Guo
    Department of Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA
    Cancer Cell 10:309-19. 2006
    ....
  18. pmc Overload of the heat-shock protein H11/HspB8 triggers melanoma cell apoptosis through activation of transforming growth factor-beta-activated kinase 1
    B Li
    Department of Pharmacology, University of Maryland School of Medicine, Baltimore, MD 21201, USA
    Oncogene 26:3521-31. 2007
    ..The data indicate that H11/HspB8 overload causes melanoma growth arrest and apoptosis through TAK1 activation and suggest that H11/HspB8 is a promising molecular therapy target...
  19. pmc First pharmacophore-based identification of androgen receptor down-regulating agents: discovery of potent anti-prostate cancer agents
    Puranik Purushottamachar
    Department of Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine, 685 West Baltimore Street, Baltimore, MD 21201 1559, USA
    Bioorg Med Chem 15:3413-21. 2007
    ..5-212 microM). Five of these molecules strongly inhibited the growth of human prostate LNCaP cells. These novel compounds may be used as leads to develop other novel anti-prostate cancer agents...
  20. pmc Genetic polymorphisms, hormone levels, and hot flashes in midlife women
    Chrissy Schilling
    Department of Epidemiology and Preventive Medicine, University of Maryland School of Medicine, Baltimore, Maryland, USA
    Maturitas 57:120-31. 2007
    ..Thus, the objective of this study was to examine whether sex steroid hormone levels and genetic polymorphisms in hormone biosynthesis and degradation enzymes are associated with the risk of hot flashes...
  21. ncbi Relation of body mass and sex steroid hormone levels to hot flushes in a sample of mid-life women
    C Schilling
    University of Maryland School of Medicine, Baltimore, Maryland, USA
    Climacteric 10:27-37. 2007
    ....
  22. pmc Current alcohol use, hormone levels, and hot flashes in midlife women
    Chrissy Schilling
    Program in Toxicology, University of Maryland School of Medicine, Baltimore, Maryland, USA
    Fertil Steril 87:1483-6. 2007
    ..Current alcohol use is associated with a lower risk of hot flashes through a mechanism that does not include changes in sex steroid hormone levels...
  23. pmc Synthesis and biological evaluations of putative metabolically stable analogs of VN/124-1 (TOK-001): head to head anti-tumor efficacy evaluation of VN/124-1 (TOK-001) and abiraterone in LAPC-4 human prostate cancer xenograft model
    Robert D Bruno
    Department of Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine, 685 West Baltimore Street, Baltimore, MD 21201, USA
    Steroids 76:1268-79. 2011
    ..These studies further demonstrate the efficacy of 5 in a clinically relevant prostate cancer model and justify its current clinical development as a potential treatment of prostate cancer...
  24. pmc Disruption of NAD(P)H:quinone oxidoreductase 1 gene in mice leads to 20S proteasomal degradation of p63 resulting in thinning of epithelium and chemical-induced skin cancer
    B A Patrick
    Department of Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine, Baltimore, MD 21201, USA
    Oncogene 30:1098-107. 2011
    ..These data suggest that NQO1 controls stabilization of p63 and progression towards keratinocyte differentiation leading to normal skin development and presumably skin carcinogenesis...
  25. ncbi Adaptive responses and latent costs of multigeneration cadmium exposure in parasite resistant and susceptible strains of a freshwater snail
    Christopher J Salice
    The Institute of Environmental and Human Health, Texas Tech University, Box 41163, Lubbock, TX 79409 1163, USA
    Ecotoxicology 19:1466-75. 2010
    ..Adaptation to prior selection pressures can influence subsequent adaptation to anthropogenic stresses and may have associated costs that reduce fitness in novel environments...
  26. pmc Pretreatment of Guinea pigs with galantamine prevents immediate and delayed effects of soman on inhibitory synaptic transmission in the hippocampus
    Elena A Alexandrova
    Department of Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine, 655 W Baltimore St, Baltimore, MD 21201, USA
    J Pharmacol Exp Ther 334:1051-8. 2010
    ..Pretreatment with galantamine prevented soman-induced changes in IPSCs. Counteracting the effects of soman on inhibitory transmission can be an important determinant of the antidotal effectiveness of galantamine...
  27. pmc Epigenetic modifications induced by RGC-32 in colon cancer
    Sonia I Vlaicu
    Department of Neurology, University of Maryland School of Medicine, Baltimore, MD 21201, USA
    Exp Mol Pathol 88:67-76. 2010
    ..These data suggest that RGC-32 may contribute to the development of colon cancer by regulating chromatin assembly...
  28. pmc The HSV-2 mutant DeltaPK induces melanoma oncolysis through nonredundant death programs and associated with autophagy and pyroptosis proteins
    A G Colunga
    Department of Pharmacology and Experimental Therapeutics, University of Maryland, School of Medicine, Baltimore, MD 21201 1559, USA
    Gene Ther 17:315-27. 2010
    ..5% of the LM melanoma xenografts at 5 months after treatment termination. The data indicate that DeltaPK is a promising virotherapy for melanoma that functions through virus-induced programmed cell death pathways...
  29. pmc Response gene to complement 32 is required for C5b-9 induced cell cycle activation in endothelial cells
    Matthew Fosbrink
    Department of Neurology, University of Maryland, School of Medicine, Baltimore, MD 21201, USA
    Exp Mol Pathol 86:87-94. 2009
    ..All these data together suggest that cell cycle induction by C5b-9 in AEC is RGC-32 dependent and this is in part through regulation of Akt and growth factor release...
  30. ncbi Demographic responses to multigeneration cadmium exposure in two strains of the freshwater gastropod, Biomphalaria glabrata
    Christopher J Salice
    Chesapeake Biological Laboratory, University of Maryland Center for Environmental Science, Solomons, MD 20688, USA
    Arch Environ Contam Toxicol 56:785-95. 2009
    ..Changes in lambda over the course of the three-generation exposure suggest that acclimation and/or adaptation to cadmium may have occurred, particularly in NMRI at the high cadmium exposure level...
  31. pmc Pulse-oximetry accurately predicts lung pathology and the immune response during influenza infection
    David Verhoeven
    Department of Surgery, University of Maryland School of Medicine, Baltimore, MD 21210, USA
    Virology 390:151-6. 2009
    ..We found blood oxygen levels to be a more accurate assessment than weight-loss morbidity in predicting lung pathology in hosts infected with different viral doses, and in assessing immune-mediated viral clearance in the lung...