Identifying the Origins, Prevalence and Toxicity of Endogenous Formaldehyde

Formaldehyde is a ubiquitous reactive aldehyde that is present in our environment. However, a significant amount of formaldehyde is produced in our bodies probably as a consequence of metabolism. We discovered that we possess a two-tier protection mechanism (aldehyde detoxification and DNA repair) that prevents this endogenous formaldehyde from causing lasting damage to our cells. We also discovered that the detoxification of formaldehyde creates a single carbon unit that the cell uses to make nucleotides. Other than this, we know very little about the biology of endogenous formaldehyde. The purpose of this research proposal is to address this, in the first instance we want to measure and detect endogenous formaldehyde in serum and in cells . We will also identify specific biomarkers for formaldehyde exposure in DNA. We will use CRISPR Cas9 genetic screens in cell lines to identify the metabolic sources of endogenous formaldehyde. Ultimately we want to further understand how endogenous formaldehyde damages vital cells like blood stem cells, liver, kidney and brain cells in mice. In addition we will use biased approaches that indicate that protection against formaldehyde is more complex than we thought and we will perform genetic screens to identify new formaldehyde protection mechanisms.