Grant: Project Grant

The epigenome is the layer of protein modifications to DNA and the proteins that assemble DNA into the nucleus known as histones. Together, these epigenetic modifications to the DNA and histones as well as proteins that anchor the DNA to the nucleus organize DNA into a 3-dimensional (3D) structure that allows some genes to be expressed and others to be silent, depending on the cell type. Thus, the epigenome is responsible for a heart muscle cell to express genes and proteins important to the heart muscle rather than genes and proteins expressed by bone cells. Aged and diseased cells lose their epigenetic modifications, leading to an altered epigenome, loss of cell identity, and cellular function. Thus, vascular cells of the heart can begin expressing bone proteins leading to "hardening of the arteries", also known as atherosclerosis. Importantly, many epigenetic modifications are reversible using drugs. In this project, we generated stem cells from patients with a rare disorder known as Progeria, in which the vasculature and other organs age very fast and the patients suffer heart attacks and stroke in their teen years due to hardening of the arteries. Underlying this vascular degeneration are DNA damage, rapid cellular aging and loss of the epigenetic modifications to the vascular cells, which we also find in the vascular cells grown from the Progeria patient stem cells. We will piece together the molecular mechanisms driving these defects using the Progeria patient stem cell-derived vascular cells. We will then test these mechanisms in tissue isolated from organ donors and patients with heart disease following surgical intervention to determine whether the Progeria patient cells model normative vascular aging and pathogenesis. We will also test the abnormal cellular behaviour using drugs that target the epigenome, thereby potentially identifying a new drug to treat vascular and heart disease.