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(http://www.niehs.nih.gov//portfolio/index.cfm?do=portfolio.grantdetail&&grant_number=R01ES033531&format=word)
| Principal Investigator: Srivastava, Sanjay | |
|---|---|
| Institute Receiving Award | University Of Louisville |
| Location | Louisville, KY |
| Grant Number | R01ES033531 |
| Funding Organization | National Institute of Environmental Health Sciences |
| Award Funding Period | 21 Feb 2024 to 30 Nov 2028 |
| DESCRIPTION (provided by applicant): | Abstract: Benzene is a ubiquitous environmental pollutant. Natural sources of benzene include gas emissions from volcanos and forest fire. Benzene is also one of the top 20 chemicals generated by industrial sources in the United States. While levels of benzene in the ambient air are usually in low ppb range, amount of benzene in automobile exhaust and tobacco smoke can exceed 50 ppm, and occupational exposure to benzene can be as high as several hundred ppm. People living near hazardous waste sites, gasoline refineries, petrochemical industries, and gasoline fueling stations may also have high exposure to benzene. Emerging data suggest that benzene can exert cardiovascular toxicity. Our preliminary studies show that exposure to benzene exacerbates atherosclerosis, the underlying cause of most cardiovascular disease and stroke. In vitro studies show that benzene metabolite t,t-muconaldehyde induces endothelial activation (expression of adhesion molecules, leukocyte adhesion and their trans-endothelial migration, and endothelial cell apoptosis). Using RNA-seq approach, we identified several molecular targets (eNOS, SOD1, HO-1, COX-2, ATF3 etc.) by which benzene and its metabolites can exert adverse effects on endothelial functions. We also observed that heat shock proteins HSPA1A and HSPA1B induced by benzene exposure could play a protective role in benzene-induced endothelial dysfunction and atherosclerosis. Based on these observations, we hypothesize that HSPA1A and HSPA1B prevent benzene-induced exacerbation of atherogenesis by inhibiting vascular inflammation and injury. To test this hypothesis, we propose two specific aims: Aim 1 will examine how HSPA1A and HSPA1B affect benzene-induced endothelial functions (vascular relaxation, leukocyte rolling and adhesion to vascular endothelium, apoptosis) and Aim 2 will examine how endothelial cell specific overexpression of HSPA1A and HSPA1B affects benzene- induced atherosclerosis (lesion size, composition and nature). Successful completion of this project will establish a mechanistically validated model of benzene-induced endothelial dysfunction and atherosclerosis. This will provide a strong rationale to examine the association of benzene exposure with vascular dysfunctions and atherosclerosis in humans. |
| Science Code(s)/Area of Science(s) |
Primary: 41 - Cardiovascular System Secondary: 03 - Carcinogenesis/Cell Transformation |
| Publications | No publications associated with this grant |
| Program Officer | Thaddeus Schug |