Stress and infection in the mother can cause deleterious long-term effects on the foetus through the hormone cortisol and other inflammatory markers. During the acute phases of stress, a placental enzyme protects the foetus from these harmful effects by converting cortisol into inactive cortisone. When the foetus is exposed to chronically elevated cortisol and inflammatory markers, however, this protection breaks down due to decreased expression of the protective enzyme. In recent studies, we have shown that the
part of the DNA that enables production of this protective enzyme is blocked from doing so by a couple mechanisms, including one called histone acetylation.
The overall goal of this research is to determine which exact factors are blocking the DNA responsible for enabling production of the protective enzyme and then to find ways to remove the blockade without causing other problems. My project specifically will determine whether histone deacetylase (HDAC) 5, a key regulator produced at high levels by the placenta, blocks the part of the DNA enabling production of the protective placental enzyme. These results will be determined in placental cell lines in a laboratory. If HDAC5 is shown to block the DNA coding for the protective enzyme, then we will apply an HDAC5 inhibitor to prevent these effects. If successful, the same inhibitor would be used on samples collected from placentae given after Caesarian section to determine if the inhibitor drug’s affects work in whole tissue before a clinical trial is proposed.
