Grant: Project Grant

As people age, some of their blood stem cells start to carry genetic changes which allows these mutant cells to expand. This is called clonal hematopoiesis (CH). CH becomes more common with age and is linked to a higher risk of diseases like heart disease, diabetes, and blood cancers. We don't fully understand what causes CH or how it connects to inflammation and aging. One possible factor is miR-146a, a small RNA molecule that helps control inflammation. We found that as people get older, their levels of miR-146a drop. In mice, losing miR-146a causes inflammation and genetic changes similar to aging. Our early research shows that in human blood cells, low miR-146a levels are linked to inflammation and more mutations. We believe that losing miR-146a with age causes CH by allowing inflammation to increase while also making the low miR-146a cells resistant to inflammation. We also think that miR-146a loss might directly cause the genetic mutations seen in CH. In this proposal, we will study miR-146a levels in blood stem cells from healthy people of different ages. Using a mouse transplant model, we will remove miR-146a in human blood stem cells to see if this causes CH. We will test to see if removing miR-146a will result in new mutations in the blood cells. Finally, we will try to understand the mechanisms by which miR-146a results in CH. We hope to determine whether loss of miR-146a plays a key role in blood stem cell aging and CH, and find ways to slow or reverse this process. This could improve health beyond the blood system, by reducing inflammation in many organs affected by CH.