2015 Progress Report: Vanderbilt - Pittsburgh Resource for Organotypic Models for Predictive Toxicology

EPA Grant Number: R835736
Center: Vanderbilt Pittsburgh Resource for Organotypic Models for Predictive Toxicology
Center Director: Hutson, Michael Shane
Title: Vanderbilt - Pittsburgh Resource for Organotypic Models for Predictive Toxicology
Investigators: Hutson, Michael Shane , Aronoff, David , Bruner-Tran, Kaylon L. , Cliffel, David , Gough, Albert , Markov, Dmitry , McCawley, Lisa J. , McLean, John , Osteen, Kevin G. , Shotwell, Matt , Taylor, D. Lansing , Tuan, Rocky , Vernetti, Lawrence , Wikswo, John
Current Investigators: Hutson, Michael Shane , Aronoff, David , Bruner-Tran, Kaylon L. , Cliffel, David , Davidson, Jeffrey M. , Gough, Albert , Markov, Dmitry , McCawley, Lisa J. , McLean, John , Osteen, Kevin G. , Shotwell, Matt , Taylor, D. Lansing , Tuan, Rocky , Vernetti, Lawrence , Wikswo, John
Institution: Vanderbilt University , University of Pittsburgh Main Campus
EPA Project Officer: Klieforth, Barbara I
Project Period: December 1, 2014 through November 30, 2018 (Extended to November 30, 2019)
Project Period Covered by this Report: December 1, 2014 through November 30,2015
Project Amount: $6,000,000
RFA: Organotypic Culture Models for Predictive Toxicology Center (2013) RFA Text |  Recipients Lists
Research Category: Human Health , Health , Safer Chemicals

Objective:

VPROMPT’s primary objective is advancing alternative methods of chemical toxicity testing using organotypic culture models (OCMs) – 3D cultures of heterotypic cells with appropriate extracellular matrices to better approximate the in vivo cellular microenvironment. We aim to use OCMs as experimentally accessible systems of intermediate complexity to advance predictive toxicology: (1) by elucidating the scale(s) of organismal complexity that most severely confound predictions of in vivo toxicity from in vitro data sets; and (2) by elucidating the details of adverse outcome pathways from molecular initiating events to tissue-level responses. We further aim to engineer and develop OCM platforms for chemical toxicity testing that will be amenable and affordable for medium to high throughput screening.

Our three specific objectives are to:

  1. Use OCMs to identify the scale(s) of organismal complexity that most severely confound computational predictions of in vivo toxicity from in vitro data sets;
  2. Use OCMs to elucidate the details of selected Adverse Outcome Pathways (AOPs) from molecular initiating events to tissue-level responses; and
  3. Engineer and develop OCM platforms and control systems that will be amenable and affordable for medium to high throughput screening of chemical toxicity.

Progress Summary:

During this reporting period our progress includes:

  • Demonstrated transgenerational occurrence of multiple reproductive diseases linked to endometriosis after tetrachlorodibenzo-p-dioxin (TCDD) exposure of  adult female mice and introduction of organ-on-chip model to further examine interactions leading to heritable diseases.
  • Developed an internet database to design and validate microphysiological systems (MPS) as predictive of human safety liabilities. The database provides important capabilities for experimental design, data management, and analysis of safety data for a reference set of compounds combined with human organ model in vitro data. 
  • Developed a multicellular agent-based model of genital tubercle in CompuCell3D that shows important morphogenetic properties dependent on SHH, FGF 10 and androgen pathways.


Journal Articles: 43 Displayed | Download in RIS Format

Other center views: All 149 publications 39 publications in selected types All 39 journal articles
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Journal Article Alexander PG, Clark KL, Tuan RS. Prenatal exposure to environmental factors and congenital limb defects. Birth Defects Research, Part C, Embryo Today: Reviews 2016;108(3):243-273. R835736 (2015)
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  • Journal Article Anders AP, Gaddy JA, Doster RS, Aronoff DM. Current concepts in maternal-fetal immunology: recognition and response to microbial pathogens by decidual stromal cells. American Journal of Reproductive Immunology 2017;77(3):e12623 (14 pp.). R835736 (2016)
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  • Journal Article Auner AW, Tasneem KM, Markov DA, McCawley LJ, Hutson MS. Chemical-PDMS Binding Kinetics and Implications for Bioavailability in microfluidic Devices. Lab on a Chip 2019;19(5):864-874 R835736 (2018)
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  • Journal Article Auner AW, Kazi M. Tasneem KM, Markov DA, McCawley LJ, Hutson MS. Chemical-PDMS binding kinetics and implications for bioavailability in microfluidic devices. Lab on a Chip 2019;19(5):864-874 R835736 (2018)
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  • Journal Article Bruner-Tran KL, Duleba AJ, Taylor HS, Osteen KG. Developmental toxicant exposure is associated with transgenerational adenomyosis in a murine model. Biology of Reproduction 2016;95(4):73 (10 pp.). R835736 (2015)
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  • Journal Article Bruner-Tran KL, Gnecco J, Ding T, Glore DR, Pensabene V, Osteen KG. Exposure to the environmental endocrine disruptor TCDD and human reproductive dysfunction: translating lessons from murine models. Reproductive Toxicology 2017;68:59-71. R835736 (2015)
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  • Journal Article Bruner-Tran KL, Mokshagundam S, Herington JL, Osteen KG. Rodent Models of Experimental Endometriosis: Identifying Mechanisms of Disease and Therapeutic Targets. Current Women's Health Reviews 2018;14(2):173–188 R835736C003 (2018)
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  • Journal Article Cyr KJ, Avaldi OM, Wikswo JP. Circadian hormone control in a human-on-a-chip:in vitro biology’s ignored component? Experimental Biology and Medicine 2017;242(17):1714-1731. R835736 (2017)
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  • Journal Article Ding T, Lambert LA, Aronoff DM, Osteen KG, Bruner-Tran KL. Sex-dependent influence of developmental toxicant exposure on group B Streptococcus -mediated preterm birth in a murine model. Reproductive Sciences 2018;25(5):662-673. R835736 (2017)
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  • Journal Article Dodds JN, May JC, McLean JA. Investigation of the complete suite of the leucine and isoleucine isomers: toward prediction of ion mobility separation capabilities. Analytical Chemistry 2017;89(1):952-959. R835736 (2015)
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  • Journal Article Gnecco JS, Anders AP, Cliffel D, Pensabene V, Rogers LM, Osteen K, Aronoff DM. Instrumenting a fetal membrane on a chip as emerging technology for preterm birth research. Current Pharmaceutical Design 2017;23(40):6115-6124. R835736 (2016)
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  • Journal Article Gnecco JS, Pensabene V, Li DJ, Ding T, Hui EE, Bruner-Tran KL, Osteen KG. Compartmentalized culture of perivascular stroma and endothelial cells in a microfluidic model of the human endometrium. Annals of Biomedical Engineering 2017;45(7):1758-1769. R835736 (2017)
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  • Journal Article Gnecco JS, Pensabene V, Li DJ, Ding T, Hui EE, Bruner-Tran KL, Osteen KG. Compartmentalized culture of perivascular stroma and endothelial cells in a microfluidic model of the human endometrium. Annals of Biomedical Engineering 2017;45(7):1758-1769. R835736 (2015)
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  • Journal Article Gnecco JS, Ding T, Smith C, Lu J, Bruner-Tran KL, Osteen KG. Hemodynamic forces enhance decidualization via endothelial-derived prostaglandin E2 and prostacyclin in a microfluidic model of the human endometrium. Human Reproduction 2019;43(4):702-714 R835736C003 (2018)
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  • Journal Article Gough A, Vernetti L, Bergenthal L, Shun TY, Taylor DL. The MicroPhysiology Systems Database for analyzing and modeling compound interactions with human and animal organ models. Applied In Vitro Toxicology 2016;2(2):103-117. R835736 (2015)
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  • Journal Article Gough A, Vernetti L, Bergenthal L, Shun TY, Taylor DL. The MicroPhysiology Systems Database for analyzing and modeling compound interactions with human and animal organ models. Applied In Vitro Toxicology 2016;2(2):103-117. R835736 (2017)
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  • Journal Article Gough A, Vernetti L, Bergenthal L, Shun TY, Taylor DL. The MicroPhysiology Systems Database for analyzing and modeling compound interactions with human and animal organ models. Applied In Vitro Toxicology 2016;2(2):103-117. R835736 (2015)
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  • Journal Article Hutson MS, Alexander PG, Allwardt V, Aronoff DM, Bruner-Tran KL, Cliffel DE, Davidson JM, Gough A, Markov DA, McCawley LJ, McKenzie JR, McLean JA, Osteen KG, Pensabene V, Samson PC, Senutovitch NK, Sherrod SD, Shotwell MS, Taylor DL, Tetz LM, Tuan RS, Vernetti LA, Wikswo JP. Organs-on-chips as bridges for predictive toxicology. Applied In Vitro Toxicology 2016;2(2):97-102. R835736 (2015)
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  • Journal Article Hutson MS, Leung MCK, Baker NC, Spencer RM, Knudsen TB. Computational model of secondary palate fusion and disruption. Chemical Research in Toxicology 2017;30(4):965-979. R835736 (2015)
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  • Journal Article Iannetti L, D'Urso G, Conoscenti G, Cutri E, Tuan RS, Raimondi MT, Gottardi R, Zunino P. Distributed and Lumped Parameter Models for the Characterization of High Throughput Bioreactors. PLoS One 2016;11(9):e0162774 (25 pp.). R835736 (2016)
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  • Journal Article Karolak A, Markov DA, McCawley LJ, Rejniak KA. Towards personalized computational oncology: from spatial models of tumour spheroids, to organoids, to tissues. Journal of the Royal Society Interface 2018;15(138):20170703. R835736 (2018)
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  • Journal Article Kimmel DW, Rogers LM, Aronoff DM, Cliffel DE. Prostaglandin E2 regulation of macrophage innate immunity. Chemical Research in Toxicology 2016;29(1):19-25. R835736 (2016)
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  • Journal Article Lee-Montiel FT, George SM, Gough AH, Sharma AD, Wu J, DeBiasio R, Vernetti LA, Taylor DL. “Control of oxygen tension recapitulates zone-specific functions in human liver microphysiology systems. Exp Biol Med 2017;242(16):1617-1632. R835736C004 (2018)
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  • Journal Article Leung MC, Hutson MS, Seifert AW, Spencer RM, Knudsen TB. Computational modeling and simulation of genital tubercle development. Reproductive Toxicology 2016;64:151-161. R835736 (2015)
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  • Journal Article Leung MCK, Hutson MS, Seifert AW, Spencer RM, Knudsen TB. Computational modeling and simulation of genital tubercle development. Reproductive Toxicology 2016;64:151-161. R835736 (2017)
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  • Journal Article Li X, George SM, Vernetti L, Gough AH, Taylor DL. A glass-based, continuously zonated and vascularized human liver acinus microphysiological system (vLAMPS) designed for experimental modeling of diseases and ADME/TOX. Lab on a Chip 2018;21;18(17):2614-2631 R835736 (2018)
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  • Journal Article May JC, Morris CB, McLean JA. Ion mobility collision cross section compendium. Analytical Chemistry 2017;89(2):1032-1044. R835736 (2016)
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  • Journal Article Rogers JM, Anders AP, Doster RS, Gill EA, Gnecco JS, Holley JM, Randis TM, Ratner AJ, Gaddy JA, Osteen K, Arnoff DM. Decidual stromal cell-derived PGE(2) regulates macrophage responses to microbial threat. American Journal of Reproductive Immunology 2018;80(4). R835736C003 (2018)
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  • Journal Article Senutovitch N, Vernetti L, Boltz R, DeBiasio R, Gough A, Taylor DL. Fluorescent protein biosensors applied to microphysiological systems. Experimental Biology and Medicine 2015;240(6):795-808. R835736 (2015)
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  • Journal Article Soto-Gutierrez A, Gough A, Vernetti LA, Taylor DL, Monga SP. Pre-clinical and clinical investigations of metabolic zonation in liver diseases: the potential of microphysiology systems. Experimental Biology and Medicine 2017;242(16):1605-1616. R835736 (2017)
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  • Journal Article Stocks MM, Crispens MA, Ding T, Mokshagundam S, Bruner-Tran KL, Osteen KG. Therapeutically targeting the inflammasome product in a chimeric model of endometriosis-related surgical adhesions. Reproductive Sciences 2017;24(8):1121-1128. R835736 (2015)
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  • Journal Article Vernetti LA, Senutovitch N, Boltz R, DeBiasio R, Shun TY, Gough A, Taylor DL. A human liver microphysiology platform for investigating physiology, drug safety, and disease models. Experimental Biology and Medicine 2016;241(1):101-114. R835736 (2015)
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  • Journal Article Vernetti L, Gough A, Baetz N, Blutt S, Broughman JR, Brown JA, Foulke-Abel J, Hasan N, In J, Kelly E, Kovbasnjuk O, Repper J, Senutovitch N, Stabb J, Yeung C, Zachos NC, Donowitz M, Estes M, Himmelfarb J, Truskey G, Wikswo JP, Taylor DL. Functional coupling of human microphysiology systems: intestine, liver, kidney proximal tubule, blood-brain barrier and skeletal muscle. Scientific Reports 2017;7:42296 (14 pp.). R835736 (2017)
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  • Journal Article Vernetti LA, Vogt A, Gough A, Taylor DL. Evolution of experimental models of the liver to predict human drug hepatotoxicity and efficacy. Clinics in Liver Disease 2017;21(1):197-214. R835736 (2015)
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  • Journal Article Vernetti L, Gough A, Baetz N, Blutt S, Broughman JR, Brown JA, Foulke-Abel J, Hasan N, In J, Kelly E, Kovbasnjuk O, Repper J, Senutovitch N, Stabb J, Yeung C, Zachos NC, Donowitz M, Estes M, Himmelfarb J, Truskey G, Wikswo JP, Taylor DL. Functional coupling of human microphysiology systems: intestine, liver, kidney proximal tubule, blood-brain barrier and skeletal muscle. Scientific Reports 2017;7:42296 (15 pp.). R835736 (2015)
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  • Journal Article Vernetti L, Gough A, Baetz N, Blutt S, Broughman JR, Brown JA, Foulke-Abel J, Hasan N, In J, Kelly E, Kovbasnjuk O, Repper J, Senutovitch N, Stabb J, Yeung C, Zachos NC, Donowitz M, Estes M, Himmelfarb J, Truskey G, Wikswo JP, Taylor DL. Functional coupling of human microphysiology systems: intestine, liver, kidney proximal tubule, blood-brain barrier and skeletal muscle. Scientific Reports 2017;7:42296 (14 pp.). R835736 (2018)
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  • Journal Article Vernetti L, Gough A, Baetz N, Blutt S, Broughman JR, Brown JA, Foulke-Abel J, Hasan N, In J, Kelly E, Kovbasnjuk O, Repper J, Senutovitch N, Stabb J, Yeung C, Zachos NC, Donowitz M, Estes M, Himmelfarb J, Truskey G, Wikswo JP, Taylor DL. Functional coupling of human microphysiology systems: intestine, liver, kidney proximal tubule, blood-brain barrier and skeletal muscle. Scientific Reports 2017;7:42296 (15 pp.). R835736 (2015)
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  • Journal Article Vernetti L, Gough A, Baetz N, Blutt S, Broughman JR, Brown JA, Foulke-Abel J, Hasan N, In J, Kelly E, Kovbasnjuk O, Repper J, Senutovitch N, Stabb J, Yeung C, Zachos NC, Donowitz M, Estes M, Himmelfarb J, Truskey G, Wikswo JP, Taylor DL. Functional coupling of human microphysiology systems: intestine, liver, kidney proximal tubule, blood-brain barrier and skeletal muscle. Scientific Reports 2017;7:42296 (14 pp.). R835736 (2018)
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  • Journal Article Vernetti L, Gough A, Baetz N, Blutt S, Broughman JR, Brown JA, Foulke-Abel J, Hasan N, In J, Kelly E, Kovbasnjuk O, Repper J, Senutovitch N, Stabb J, Yeung C, Zachos NC, Donowitz M, Estes M, Himmelfarb J, Truskey G, Wikswo JP, Taylor DL. Functional coupling of human microphysiology systems: intestine, liver, kidney proximal tubule, blood-brain barrier and skeletal muscle. Scientific Reports 2017;7:42296 (15 pp.). R835736 (2015)
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  • Journal Article Watson DE, Hunziker R, Wikswo JP. Fitting tissue chips and microphysiological systems into the grand scheme of medicine, biology, pharmacology, and toxicology. Experimental Biology and Medicine 2017;242(16):1559-1572. R835736 (2017)
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  • Journal Article Wikswo JP. Looking to the future of organs-on-chips: interview with Professor John Wikswo. Future science OA 2017;3(2):FSO163. R835736 (2018)
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  • Journal Article Miller DR, McClain ES, Cliffel DE. Electrochemical Microphysiometry Detects Cellular Glutamate Up-take. Journal of The Electrochemical Society 2018;165(12):G3120-G3124. R835736C005 (2018)
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  • Journal Article Ding T et al, 2018. Reproductive Sciences 25(5):662-673 Bruner-Tran KL et al, 2018. Current Women’s Health Rev Jun;14(2):173-188 Rogers et al, 2018. American Journal of Reproductive Immunology Oct;80(4):e13032. R835736 (2018)
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    not available

    Relevant Websites:

    Vanderbilt-Pittsburgh Resource for Organotypic Models for Predictive Toxicology (VPROMPT) Exit
    Vanderbilt Institute for Integrative Biosystems Research and Education (VIIBRE) Exit
    Microphysiology Systems Database | University of Pittsburgh Drug Discovery Institute Exit
    Center for Cellular & Molecular Engineering | University of Pittsburgh Exit

    Progress and Final Reports:

    Original Abstract
  • 2016 Progress Report
  • 2017 Progress Report
  • 2018 Progress Report
  • Subprojects under this Center: (EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).
    R835736C001 Mammosphere Bioreactor For Life-Stage Specific Toxicology
    R835736C002 Organotypic Culture Model to Analyze Developmental LimbMalformationsResulting from Toxicant/Teratogen Exposure
    R835736C003 Validating a fetal membrane on a chip model for characterizing reproductive toxicant exposure risks
    R835736C004 Organotypic Liver Model for Predictive Human Toxicology and Metabolism
    R835736C005 Systems Engineering & Analysis for Organotypic Culture Models