Division of Comparative Medicine
Department of Biological Engineering
Department of Biological Engineering
Project 1: Assessment of the Health Effects of N-Nitrosamines and Development of Disease Mitigation Strategies
Goal
The Goal of Project 1 is to create and leverage a genetically engineered mouse model and a cell-based biosensor platform. The mouse model is deficient in key DNA repair proteins and harbors integrated substrates to detect point mutations and recombination events. These mice are being used to study NDMA exposure under both acute and chronic exposure conditions (e.g., NDMA in drinking water) in order to reveal the short term (omics data), medium term (mutations and inflammation) and long term (cancer) consequences of exposure and to elucidate the role of DNA repair proteins in suppressing these effects. For the cell-based platform, we are using chemicals to trap DNA repair intermediates as a way to know if a particular exposure is putting pressure on specific DNA repair pathways.
Impact
The genetically engineered mice are anticipated to be acutely sensitive to NDMA, and so we are calling these mice the “canary in a coal mine genetically engineered mice” or C-GEM. Using these mice, we will be able to learn if longer-term lower-dose exposures have the potential to cause mutations and cancer, and we will learn the role of DNA repair in preventing these processes. With our cell-based platform, we can test different kinds of N-nitrosamines for their DNA damaging potential, which is important because DNA damage can cause mutations that drive cancer. Project 1 leaders and trainees, in collaboration with the CEC, will also listen to and work with community members and tribes to develop novel hands-on teaching curricula that explain key concepts in biology that underlie their research activities.
The Project
A weakness in the literature is the lack of epidemiological studies that directly test the impact of NDMA on people’s health (this is due to the technical difficulty of measuring NDMA). To learn about molecular mechanisms and to contribute to the development of predictive biomarkers, we will initially study the biological impact of long-term low-dose exposure using a level known to cause cancer in mice (1 ppb). Our hypothesis is that C-GEM mice will make it possible to reveal the impact of NDMA in drinking water on systems-level responses, mutations, and cancer under environmentally relevant levels.
- Aim 1: Use the C-GEM mice to explore the impact of NDMA exposure for younger versus older animals, and to compare acute exposure to chronic exposure in drinking water.
- Aim 2: To use chemical-genetics to create Chem-Sense Cells as a novel biosensor for DNA damage induced by N-nitrosamines present at Superfund Sites.
- Aim 3: To leverage the C-GEM mice to reveal the biological mechanisms by which probiotics modulate the biological effects of NDMA.
