Cancer & Radiation
The Structural Cell Biology of DNA Repair Machines (SBDR) is a multi-investigator (21), multi-institutional (15), interdisciplinary effort optimized to meet the extreme challenges of characterizing transient complexes and conformations acting in DR responses. The program will integrate knowledge of DR proteins and pathways by analyzing keystone complexes functioning as regulatory nodes in complex cellular responses to DNA damage. It will focus on crossroads for DR pathways, especially those connecting DR with replication, recombination, and damage signaling.
This program, lead by Gary Karpen, has been developed to address the similarly named Scientific Focus Area (SFA) identified by the U.S. Department of Energy (DOE). The program, entitled "A Systems Biology Approach to Assessment of Responses to Low Dose / Low Dose-Rate Ionizing Radiation," uses a strategy that integrates systems genetics and discovery approaches with mechanistic information from all levels of biological organization – molecules, cells, tissues and animal models – to address key questions concerning the effects on human health of low dose, low dose-rate exposure to ionizing radiation.
The emphasis is on biological mechanisms that contribute to carcinogenic risk, especially for breast cancer. The approach considers effects both on the epithelial cells that are at risk of malignancy and on stromal cells that do not become malignant but which impact radiation-induced carcinogenesis through changes in the tissue microenvironment. The central issues being addressed are to what extent responses to low doses differ from high dose responses and can alter the response to subsequent exposures, the mechanisms and genetic determinants responsible for such effects, and their consequences with respect to deviation from a linear dose response for carcinogenesis.
Four inter-connected SFA research components coordinately investigate low dose responses through complementary studies using both in vivo mouse models of differing radiosensitivity and comparative culture systems for mammary-derived mouse and human cells: component one focuses on non-linear and adaptive response mechanisms in mammary cell culture models; component two investigates mammary tissue radiation response phenotypes predicted by transcriptome responses; component three uses systems genetics and organotypic culture to understand differences in susceptibility to low-dose radiation-induced mammary tumors; the fourth component, the Integration Hub, provides support for advanced technologies and integrative data analysis applied across all components.