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Elucidation of the immune response and of the impact of the microbiome in murine calcific aortic valve stenosis

Aortic valve stenosis (AS) is a progressive inflammatory disease that leads to valve remodeling and destruction, impeding blood ejection from the left ventricle. The valve is composed of stroma cells, myofibroblasts, and endothelial cells and also contains numerous immune cells that contribute to the destructive inflammatory processes in AS. Myeloid cells like dendritic cells, monocytes, and macrophages play important roles, and recent evidence suggests a role for T cells. The complex cross-talk between immune cells, valvular endothelial cells, and VICs is incompletely understood. Furthermore, recent studies have highlighted the impact of the gut microbiota and of the salt content of our diet in atherosclerosis, hypertension, and heart failure. The molecular mechanisms by which gut microbiota and dietary salt implement the development of AS has not been addressed yet.

We hypothesize that adverse tissue remodeling and ossification in AS are driven by immune responses and can be influenced by dietary salt and by the gut microbiome.

In Aim 1, we will characterize the roles of myeloid immune cell subsets in experimental AS, by examining the course of disease in the established AS mouse model using mice lacking specific immune cell subsets or their effector molecules. Aim 2 will address the roles of T cell subsets in AS. Aim 3 will focus on the influence of the gut microbiome on the progression of AS in mice treated with antibiotics and in gnotobiotic mice. In Aim 4, we will study the effects of a high-salt diet on the course of AS, as well as its impact on in the immune effectors involved and on the intestinal microbiome. In all four aims, we will validate the mechanistic data gained by analyzing human blood, valve, and stool samples to elucidate the impact of the immune response and the individual microbiome in patients suffering from AS. Our long-term goal is to identify novel pathogenic players in AS as potential targets for future therapies to improve disease progression and clinical outcome.



A01 Hypothesis: Adverse tissue remodeling in AS are driven by the innate and adaptive immune response and can be influenced by the gut microbiome

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