Grantee Research Project Results
2008 Progress Report: Endothelial Cell Responses to PM—In Vitro and In Vivo
EPA Grant Number: R832414C002Subproject: this is subproject number 002 , established and managed by the Center Director under grant R832414
(EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).
Center: UC Davis Center for Children's Environmental Health and Disease Prevention
Center Director: Van de Water, Judith
Title: Endothelial Cell Responses to PM—In Vitro and In Vivo
Investigators: Wilson, Dennis , Rutledge, John
Current Investigators: Wilson, Dennis , Barakat, Abdul , Anastasio, Cort , Tablin, Fern , Rutledge, John
Institution: University of California - Davis
EPA Project Officer: Chung, Serena
Project Period: October 1, 2005 through September 30, 2010 (Extended to September 30, 2011)
Project Period Covered by this Report: October 1, 2007 through September 30,2008
RFA: Particulate Matter Research Centers (2004) RFA Text | Recipients Lists
Research Category: Human Health , Air
Objective:
Approach:
We will evaluate the transcriptional responses to environmentally derived particulate matter in human endothelial cell cultures in the context of functional models of inflammation and coagulation system activation. Microarray transcriptional screening of environmental samples collected in the SJV Inhalation Exposure Project will identify characteristic endothelial cell responses. Based on these data, key gene transcripts with potential influence on pro-inflammatory and hemostatic activities will be used to develop a panel of RT-PCR based transcriptional assays. We will study the functional significance of these activities by examining PM-induced alterations in the endothelial cell permeability barrier and inflammatory cell interactions with the endothelium of intact vessels. To determine the significance of endothelial cell reactions in vivo, we will extrapolate our understanding of the endothelial cell transcriptional response to determine whether and where similar responses occur in concentrated ambient particle (CAPs) exposed animals using histology, laser capture microdissection, and RT-PCR assays of potential target organs and vessels. We will extend these results to cardiovascular disease using mice as models. We will determine whether PM selectively accumulates in atherosclerotic plaque from isolated arteries of predisposed ApoE-/- mice and determine with similar in vivo laser capture studies whether this selectively upregulates proinflammatory reactions in plaque of CAPs-exposed atherosclerotic mice.
Progress Summary:
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Systemic Coagulation markers after intratracheal instillation of collected ambient PM 2.5: Supported also by CARB (Tablin & Wilson).
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Evaluation of Monocyte Platelet and Endothelial cell interface in systemic coagulation in vitro.
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Comparison of ROS generating capacity of differing source collected ambient PM 2.5 (Anastasio) vs. ROS generation and Nrf2signaling in cultured cells.
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More focused evaluation of pro-coagulant mechanisms and activities in plasma in field exposure studies IL-11
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Thrombopoetin
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Tissue Factor
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Thrombospondin
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Evaluate cytokines in BAL in collaboration with Project 3 and inflammatory mediator expression in airway epithelium and vasculature. Extend these studies to markers of ROS response elements.
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Multiplex assay of endothelial cell barrier functional responses to synthetic and collected PM.
Expected Results:
Microarray studies should provide significant insight into the specificity of responses to particulate matter. Signal transduction and endothelial cell functional studies will answer similar questions about specificity. These should help distinguish between non-specific oxidant injury and potential interference with specific endothelial cell activation pathways. The combination of gene and protein responses assayed in CAPs-exposed animals should provide significant evidence of PM-induced vascular proinflammatory and coagulant responses in normal tissues. Experiments with atheromatous mice exposed to CAPs should determine whether specific accumulation of PM in altered regions of vascular wall could contribute to the initiation of plaque rupture. They also will address the possibility that atheromatous plaque might be selectively susceptible to the induction of inflammatory responses to circulating PM.
Journal Articles:
No journal articles submitted with this report: View all 15 publications for this subprojectSupplemental Keywords:
aerosol, ozone, exposure, health effects, human health, metabolism, sensitive populations, infants, children, PAH, metals, oxidants, agriculture, transportation,, RFA, Health, Scientific Discipline, Air, particulate matter, Environmental Chemistry, Health Risk Assessment, Epidemiology, Risk Assessments, ambient aerosol, lung injury, acute cardiovascular effects, long term exposure, toxicology, lung disease, air toxics, airway disease, airborne particulate matter, ambient particle health effects, human exposure, inhalation toxicology, epidemiological studies, concentrated air particles, vascular dysfunction, microarray studies, PM, cardiovascular diseaseProgress and Final Reports:
Original AbstractMain Center Abstract and Reports:
R832414 UC Davis Center for Children's Environmental Health and Disease Prevention Subprojects under this Center: (EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).
R832414C001 Project 1 -- Pulmonary Metabolic Response
R832414C002 Endothelial Cell Responses to PM—In Vitro and In Vivo
R832414C003 Project 3 -- Inhalation Exposure Assessment of San Joaquin Valley Aerosol
R832414C004 Project 4 -- Transport and Fate Particles
R832414C005 Project 5 -- Architecture Development and Particle Deposition
The perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Conclusions drawn by the principal investigators have not been reviewed by the Agency.
Project Research Results
- Final Report
- 2010 Progress Report
- 2009 Progress Report
- 2007 Progress Report
- 2006 Progress Report
- Original Abstract
9 journal articles for this subproject
Main Center: R832414
128 publications for this center
64 journal articles for this center