Grants and Contracts Details
Description
Arsenic remains a top environmental concern in the United States as well as world-wide because of its global
existence and serious health impacts. Epidemiological studies provide ample evidence that arsenite exposure is
associated with the increased incidence of skin and lung cancers. The scope of the parent grant addresses the
relation of reactive oxygen species (ROS) generation and skin carcinogenesis due to arsenite exposure in both
the human keratinocytes and the mouse skin models. While the scope of current competitive revision seeks to
evaluate the contribution and molecular mechanisms of linking the arsenite-induced chronic inflammation to lung
carcinogenesis both in vitro and in vivo, this competitive revision seeks to expand the original scope of study
from ROS generation in the mediation of skin carcinogenesis, to identification of the molecular mechanisms that
link arsenite-induced chronic inflammation to lung tumorigenicity in vitro and in vivo in cellular as well as animal
response to arsenite exposure. Although both the parent grant and the current competitive revision propose to
study the mechanisms implicated in the carcinogenic effects of arsenite exposure, this revision is specifically
intended to identify the contribution of key inflammatory mediators TNF-cz and COX-2 to arsenite-induced
development of tumorigenicity of human bronchial epithelial cells (HBECs) in vitro and in vivo, as well as the
molecular mechanisms involved in this tumorigenic process. The main hypothesis of this revision is that TNF-a
plays a central role in the formation and maintenance of sustained chronic lung inflammation and subsequently
results in the induction of lung epithelial cell tumorigenicity due to arsenic exposure. The overall goal of this
proposal is to determine role of TNF-a and COX-2 in arsenite-induced HBECs' tumorigenicity, as well as the
central role of TNF-a in the maintenance of lung chronic inflammation during arsenic exposure both in vitro and
in vivo. There are two Specific Aims proposed for this investigation: 1) To determine the contribution of TNF-ct
and COX-2 to the development of tumorigenicity of HBECs due to arsenic exposure; 2) To assess the central
role of TNF-a in arsenic-induced lung chronic inflammation and its mechanisms in vivo. Success of the revision
will facilitate our understanding of the molecular mechanism(s) of the formation and maintenance of the chronic
lung inflammatory microenvironment, and its role in lung cancer development induced by arsenic exposure. A
better understanding of those issues may provide valuable information that is needed for the designing more
effective agents for the prevention of and therapy for inflammation-associated lung cancers. Furthermore,
funding of this competitive revision will save two jobs, one part-time for Dr. Jianxiu Yu and one for Dongyun
Zhang, both of whom provide valuable expertise and are crucial for the proposed studies. The finding will also
create new training opportunity for two postdoctoral fellows in the proposed research field. Since we have most
of research tools, and research animals are either available in our laboratory or commercially, we believe that
the proposed studies will be achieved within two years.
Status | Finished |
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Effective start/end date | 2/1/06 → 12/31/11 |
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