Project 3: Remote control of hematopoiesis in cardiovascular disease

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Atherosclerosis, the underlying cause of myocardial infarction and stroke, is a lipid-driven chronic inflammatory disease characterized by lipoprotein and leukocyte accumulation in the vessel wall. With some exceptions, all leukocytes are produced in the bone marrow. Here, we will explore long-distance communication between disease locations and hematopoiesis in the bone marrow. We will identify factors secreted in the atheroma and ischemic myocardium, and then target those factors whose cognate receptor is expressed by hematopoietic stem and progenitor cells. Such an approach will reveal direct transmission lines by which effector sites might control leukocyte production, mobilization, and function. In the first aim, we will screen for secreted factors that link diseased cardiovascular microenvironments with the bone marrow. We will perform RNAseq to generate data sets for myocardial infarction and atherosclerosis to identify ligand-receptor pair expression in the same milieu. For promising candidates, we will confirm mRNA expression and protein expression with available tools. For each candidate molecule, we will follow the blueprint established with our preliminary data, adapting the strategy to profile how other factors produced in atherosclerotic lesions and in the infarcted myocardium might influence the bone marrow. In the second aim, we will elucidate long-distance mechanisms by which diseased microenvironments exert remote control of the bone marrow. We will determine how candidate factors produced in the atherosclerotic lesion and in the infarcted myocardium control processes in the bone marrow. Collectively, these experiments will identify new lines of long-distance communication between diseased sites (lesion, infarct), elucidate the underlying mechanisms, and pave the way for new therapeutic approaches for cardiovascular disease.