The Role of TLR7/8-Activating microRNAs in Obstetric Antiphospholipid Syndrome
Abstract
Many women with lupus have circulating autoantibodies called antiphospholipid antibodies. These women are at high risk for miscarriage and other pregnancy complications, like preeclampsia. Since antiphospholipid antibodies can attack the placenta, we believe they are detrimental to pregnancy by changing its normal function. However, we know very little about how these processes arise. Our overall goal is to gain a better understanding of how these pregnancy complications arise in women with antiphospholipid antibodies so that we can develop new methods of diagnosis and treatment. One of our aims is to work out how antiphospholipid antibodies cause inflammation in the placenta. For this we will investigate the role of a group of unique microRNAs which can bind and activate innate immune receptors called Toll-like receptors and trigger inflammation. Another one of our aims is to work out how antiphospholipid antibodies cause vascular injury at the maternal-fetal interface. For this we will investigate the role of placental-derived vesicles called exosomes, which can traffic to the endothelium and elicit a response. We propose that these placental exosomes carry Toll-like receptor-activating microRNAs to the endothelium which trigger vascular activation and injury. Together these studies will provide a new understanding into the way in which antiphospholipid antibodies cause miscarriage, preeclampsia, and other pregnancy complications in women with lupus. As the current therapies do not help all aspects of pregnancy, by understanding how these autoantibodies affect the function of the placenta and the vasculature, we may find new targets to develop therapies toward. Since our proposed studies address how antiphospholipid antibodies attack the placenta it is directly related to the Lupus Research Program Focus area of Determining the pathobiology of lupus disease in target human tissues including, but not limited to, imaging studies, genomics of lupus in particular tissues, and metabolomics. Since it is currently impossible to know which patients will develop these pregnancy issues, it is important to be able to determine whether a woman’s antiphospholipid antibodies are particularly harmful to the placenta, the vasculature, and pregnancy. Through our studies, we expect that we will be able to develop new ways in which we can predict whether a woman with lupus will be at risk for miscarriage or other pregnancy problems. Thus, in our final aim we will investigate the potential of circulating exosomes containing Toll-like receptor-activating microRNAs to predict pregnancy outcome in women with antiphospholipid antibodies. By the end of our 4-year study we except to have enough data to begin clinical validation and prospective studies on order to determine the early changes in exosome microRNAs seen between in patients’ antiphospholipid antibodies, lupus, and pregnancy complications. If successful, this could lead to the development of a liquid biopsy for predicting adverse pregnancy outcomes in these patients. Our proposed studies represent an unexplored area of lupus research and may be transformative by revealing novel pathways of placental and vascular damage, providing us with new therapeutic targets and predictors of pregnancy complications in women with antiphospholipid antibodies; a high risk population. Since pregnancy complications associated with antiphospholipid antibodies and lupus, such as preeclampsia, can cause short-term and long-term health problems for both the mother and child, our overall goal is to reduce the incidence of antiphospholipid antibody-associated pregnancy problems, so that that their health and wellbeing will be significantly improved.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110718
Entities
People
- Vikki Abrahams
Organizations
- United States Army
- Yale University