Description
The overall goals of this Research Area are to elucidate the underlying mechanisms of environmentally-induced carcinogenesis. The research will emphasize cellular responses to environmental stress, pro-survival and pro-death mechanisms, genomic instability incited by exposure to environmental agents such as radiation and chemicals, and the etiologies of specific environmentally induced cancers. Members of RFA2 use cell culture and animal models as well as human population-based approaches to carry out hypothesis-driven studies in these areas of research.
The Specific Aims of Research Focus Area 2 are:
- Characterize and understand cellular and organismic responses to environmental stress, including, but not limited to, DNA damage response;
- Identify mechanisms and pathways that contribute to cancer initiation, progression, and susceptibility, with a focus on cancers that reflect a strong interaction between environmental and hereditary factors in their etiologies;
- Perform human population-based studies that focus on association of polymorphisms in DNA repair, cell cycle, and other critical genes with cancer susceptibility to environmental exposures;
- Identification of novel molecular targets and new pathways that control genomic instability, with the aim of developing new strategies to protect the genome from environmental insult.
These aims will be accomplished by RFA2 members through their individual research programs in studies of gene-environment interactions, environmental stress responses, cellular mechanisms for maintaining genomic stability, and using animal models of specific cancers that reflect strong environmental and/or genetic influences in their etiologies.
Research Significance
RFA2 members share a common interest in the mechanisms of carcinogenesis, and understanding how the interaction of environment and fundamental cellular processes cause cancer. All members of this RFA have research programs which actively interrogate one or more aspects of environmental carcinogenesis, including DNA damage and repair (El-Zein, Legerski, Li, MacLeod, Mitchell, Nairn, Vasquez and Wei), transduction of damage signals through stress response pathways (Johnson, Legerski, Li, MacLeod, Wong), cell cycle modulation and apoptosis in response to environmental stress (Bratton, Johnson, Li, Tang) and development and use of experimental models for studying specific cancers and their underlying mechanisms, including melanoma and non-melanoma skin cancers (Mitchell, Nairn, Wei). In addition, the role of cell cycle modulation (Johnson) and DNA damage-signaling (Legerski, Li, Wong) genes on the maintenance of genomic stability, essential to stave off malignant transformation, are being studied. RFA2 members use a variety of experimental approaches in defining host responses to environmental stress, with the perspective of understanding one of these responses in particular - carcinogenesis - in context of its genetic factors, and using the mechanistic knowledge gained for a better understanding of paradigms for the control of genomic stability. This knowledge can be used to develop new strategies for protecting the genome from environmental insult, and better risk models for human exposures to environmental agents based on inherent genetic variabilities in the human population with respect to DNA repair capacity and other relevant parameters.
Many diseases are caused through the interaction of the environment and genetically determined responses of the organism to environmental stresses. These interactions can lead directly to specific diseases, or can ameliorate the effects of environmental exposures and thereby prevent disease. DNA damage caused by radiation or chemical exposures, for example, can directly result in genetic lesions that initiate malignant transformation. On the other hand, cellular responses to DNA damage can result in its repair, removing the proximate cause of initiation, or may result in the orchestration of the programmed death (apoptosis) of cells with DNA too heavily damaged to recover through repair mechanisms. Many cancers have etiologies that reflect the strong influence of certain environmental exposures. For example, in the common skin cancers (squamous cell and basal cell carcinomas), accumulated DNA damage from solar radiation is the initiating cause of malignant transformation, potentiated by the failure of tumor suppressor mechanisms (e.g., p53 in the case of BCC). The profound influence of the genetically defined environmental stress response to UV is evidenced by the fact that DNA repair compromised individuals (e.g., XP patients) have skin cancer incidences orders of magnitude higher than normal individuals.
Members
Nairn, Rodney Carcinogenesis, SPRD
Bratton, Shawn Pharmacology/Toxicology, UT Austin
El-Zein, Randa Epidemiology, UTMDACC
Johnson, David Carcinogenesis, SPRD
Legerski, Randy Molecular Genetics, UTMDACC
Li, Lei Experimental Radiation Oncology, UTMDACC
MacLeod, Michael Carcinogenesis, SPRD
Mitchell, David Carcinogenesis, SPRD
Tang, Dean Carcinogenesis, SPRD
Vasquez, Karen Carcinogenesis, SPRD
Wei, Qingyi Epidemiology, UTMDACC
Wong, Paul Carcinogenesis, SPRD
