Atherosclerosis is the underlying cause of cardiovascular disease (CVD). Although multifactorial, atherosclerosis is characterized by the formation of plaques comprising accumulated lipids, activated endothelial cells, leukocytes and macrophages that uptake oxidized lipids and transform in foam cells. The necrotic breakdown of atherosclerotic plaques precipitates myocardial infarction, unstable angina and stroke; which in combination represents the leading cause of death, especially in the Western hemisphere. Though the treatment with lipid-modifying drugs (such as statins) have reduced the risk of CVD, the need for new approaches that target novel pathways for the prevention of atherosclerosis are critically needed. Remarkably, the helminth parasite Schistosoma mansoni has been shown to alleviate the effects of a high fat diet and reduce cholesterol, triglycerides levels and atherosclerotic plaques in humans and in different mouse models. Ongoing studies in our lab have shown that schistosomiasis induces a profound reprogramming of the transcriptional profiles of hepatic macrophages. Furthermore, our analyses have demonstrated that schistosomiasis alters the expression profiles of genes involved in phospholipid and cholesterol pathways, and in particular the expression of important lipid metabolism proteins, such as apoC1. Therefore, I hypothesize that S.mansoni mechanism of athero-protection relies on the modulation of macrophage-derived factors like apoC1 and propose to determine whether these metabolic alterations are consequence of direct interaction between parasite antigens and vital host cells. Aim 1 of this proposal will delve into the effects of the parasite antigen to modulate apoC1 expression in host hepatic macrophages, while Aim 2 will focus on the in vivo effects of the macrophage-derived ApoC1 in modulation of atherosclerotic plaques. I will rely on genetic overexpression, in vitro cell ablation and in vivo imaging approaches to explore the beneficial effects of this helminth in the protection from CVD. My long-term goal is to understand the underlying basic mechanisms of protection to metabolic disorders by helminthes that will translate in the development of novel approaches for improving prevention and treatment of CVD. Finally, the multifaceted approaches in this proposal will provide valuable training for me to become an independent scientist.
|Program type||Predoctoral Fellowship|
|Effective start/end date||07/01/2018 → 06/30/2019|