In response to NOT-OD-09-058: NIH Announces the Availability of Recovery Act for Competitive Revision Applications;this is an application for a competitive revision to expand the scope of the aims for 5R01- ES013781-02: Mechanisms for arsenic-induced vascular disease. Chronic exposure to trivalent arsenic is well known to cause cardiovascular diseases. In the human liver, arsenic promotes vascular remodeling, portal fibrosis, and hypertension, but the molecular pathophysiology of these arsenic-induced vascular changes is unknown. More recently, arsenic exposures have been linked to metabolic, as well as cardiovascular diseases. We proposed in 5R01-ES013781-02 that arsenic effects on the highly specialized liver sinusoidal endothelial cells (LSEC) contribute to the cardiovascular pathogenesis of arsenic exposures.
The aims 5 R01-ES013781- 02 investigate the hypothesis that arsenic acts at the level of G-protein coupled cell signaling to increase NADPH oxidase oxidant generation that disrupts maintenance of liver sinusoidal LSEC fenestrations and suppression of capillarization, a process that limits lipid metabolism and protein scavenging functions.
The Specific Aims have not changed and are to determine: I. the molecular mechanism by which arsenic causes liver sinusoidal capillarization and remodeling in intact mice;II. the role of Nox2-based NADPH oxidase generated superoxide in mediating arsenic -induced phenotypic conversion of primary murine and human LSEC;and III. if an imbalance in LSEC GTPase activity mediates arsenic-stimulated remodeling of the LSEC. These studies were limited to investigating the initiation of arsenic responses within the first two weeks of in vivo exposure. Studies published in the first year of the grant provided proof of hypothesis for original aim 2 by demonstrating that arsenic failed to remodel and capilliarize the liver vasculature in mice lacking NADPH oxidase. Additional exploratory studies demonstrated that prolonged exposure to environmentally relevant levels of arsenic in drinking water caused progressive change in the genotypes of bacteria in the colon. This revision proposes two new aims that will translate these findings to investigating the hypothesis that arsenic-stimulated LSEC dysfunction and conversion of the gut microbiome result in pathogenic loss of scavenging activity, inappropriate lipid deposition in abdominal fat, and microvessel remodeling in the liver and heart.
The aims will investigate: I. investigate the hypothesis that LSEC capillarization and dysfunction caused by environmental exposure to arsenic decreases LSEC scavenging activity, increases fat deposition, and remodels cardiac microvessels;and II. investigate the impact of arsenic exposure on the gastrointestinal tract bacterial community structure and colonization profile and the role of LSEC phenotype and systemic changes on the gut microbiome. These studies will provide essential connection of the basic studies 5R01-ES013781- 02 with disease outcomes and greatly accelerate identifying the role of LSEC dysfunction and gut microbiome changes in the etiology of environmentally-derived metabolic and vascular diseases.
It is known that arsenic causes cardiovascular and metabolic-linked diseases in millions of people worldwide;however, the mechanisms for the health risks of chronic low level arsenic exposures are poorly understood. These studies will use human-relevant environmental arsenic exposures of intact mice and primary isolates of mouse and human cells to reveal the molecular pathology underlying arsenic-induced vascular remodeling in the liver and systemic vascular beds to define a novel mode of action through which low, chronic arsenic exposures promote vascular diseases. In addition, these studies will examine how arsenic effects on the bacterial colonies in the gastrointestinal tract influence host metabolism to influence disease progression.
Showing the most recent 10 out of 15 publications
