Mineralocorticoids have an important function during normal physiology, but increased mineralocorticoid receptor (MR) activation can cause or exacerbate a variety of diseases. Stroke is a major cause of mortality, and MR activation has a detrimental effect during ischemic stroke. MR antagonists provide beneficial effects during models of ischemic stroke independent of their blood pressure-lowering effects. We have recently shown that myeloid cells are critical targets for MR antagonists during ischemic stroke. However, cell-type- specific contribution of different myeloid cells and the mechanism by which myeloid MR exacerbates stroke is still unknown. Our laboratory has demonstrated that MR activation enhances pro-inflammatory, classical macrophage activation, whereas MR antagonism results in anti-inflammatory, alternative macrophage activation. We hypothesize that changes in macrophage activation are important in controlling the inflammatory component of stroke. The proposed studies will identify the cell-type-specific contributions and seek to identif the mechanisms by which myeloid MR activation exacerbates ischemic stroke. Furthermore, we will test whether we can enhance alternative macrophage activation with pharmacological synergy to provide additional neuroprotection during stroke.

Public Health Relevance

Our long-term goal is to delineate the mechanisms by which myeloid mineralocorticoid receptor (MR) exacerbates ischemic stroke, and to understand the role that MR regulation of macrophage polarization has during stroke. My proposed studies will help provide an understanding of the regulation of macrophage phenotypes during stroke and identify ways in which we can alter these phenotypes with pharmacological interventions.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
5F31NS077780-02
Application #
8535564
Study Section
Special Emphasis Panel (ZRG1-F01-F (20))
Program Officer
Bosetti, Francesca
Project Start
2012-07-01
Project End
2014-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
2
Fiscal Year
2013
Total Cost
$32,924
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Pharmacology
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109