Endothelial Cell Responses to PM—In Vitro and In Vivo

EPA Grant Number: R832414C002
Subproject: 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: San Joaquin Valley Aerosol Health Effects Research Center (SAHERC)
Center Director: Wexler, Anthony S.
Title: Endothelial Cell Responses to PM—In Vitro and In Vivo
Investigators: Wilson, Dennis , Rutledge, John
Current Investigators: Wilson, Dennis , Anastasio, Cort , Barakat, Abdul , Rutledge, John , Tablin, Fern
Institution: University of California - Davis
EPA Project Officer: Stacey Katz/Gail Robarge,
Project Period: October 1, 2005 through September 30, 2010 (Extended to September 30, 2011)
RFA: Particulate Matter Research Centers (2004) RFA Text |  Recipients Lists
Research Category: Health Effects , Air

Objective:

This project will determine the potential relationship between vascular disease and effects of circulating ultrafine particulate matter (PM).

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.

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.

Publications and Presentations:

Publications have been submitted on this subproject: View all 15 publications for this subprojectView all 111 publications for this center

Journal Articles:

Journal Articles have been submitted on this subproject: View all 9 journal articles for this subprojectView all 48 journal articles for this center

Supplemental 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, Health Risk Assessment, Environmental Chemistry, 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 disease

Progress and Final Reports:

2006 Progress Report
2007 Progress Report
2008 Progress Report
2009 Progress Report
2010 Progress Report
Final Report


Main Center Abstract and Reports:

R832414    San Joaquin Valley Aerosol Health Effects Research Center (SAHERC)

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