PROJECT 3: Remote control of hematopoiesis in CVD

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 with particular emphasis on the brain as the organ connecting cardiovascular tissue with the bone marrow. In two aims, we will first elucidate the role of specific brain regions in modulating myelopoiesis and atherosclerosis and then elucidate he role of specific brain regions in modulating myelopoiesis in myocardial infarction. We will build on strong published and unpublished preliminary data showing that atherosclerosis and MI influence myelopoiesis in the bone marrow, that specific regions in the brain control peripheral immune cell numbers and function and that manipulating stress centers in the brain influences bone marrow function. We will work with investigators from the other projects of the PPG, as well as with the Cores. We will employ many of our established gain and loss-of-function interventions, including chemogenetics, optogenetics, viral tracing, brain-region specific knockout mice, and cell-type specific stress hormone receptor knockout mice to investigate how different brain regions contribute to hematopoiesis in atherosclerosis and myocardial infarction. These will be combined with classical tools of immunology and vascular biology that we have used routinely over many years. 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.