The inflammatory reaction associated with cerebral ischemia contributes to the acute phase of ischemic brain damage raising the possibility that suppressing inflammation could be of therapeutic value in ischemic stroke. However, our understanding of post- ischemic inflammation is not sufficient to direct therapeutic interventions. In particular, the upstream events initiating and coordinating the expression of the cytokines and adhesion molecules that drive the infiltration of inflammatory cells into the brain remain poorly defined. The type-B scavenger receptor CD36, a multifunctional receptor expressed in blood cells, endothelium and microglia, is activated by a broad array of ligands, including """"""""danger associated molecular pattern molecules"""""""" (DAMPs) released by tissue damage. Studies during the previous funding period have established that CD36-null mice have a profound attenuation of the post-ischemic expression of inducible nitric oxide synthase and cellular infiltration, and are protected from cerebral ischemic damage. Therefore, the central hypothesis of this application is that CD36 is a key upstream receptor that is activated by stress signals and enhances brain injury by promoting the post-ischemic accumulation of inflammatory cells in the brain. We will test the following specific hypotheses: (1) CD36 is required for the post-ischemic entry into the brain of selected inflammatory cell populations that influence the outcome of cerebral ischemia;(2) CD36 induces a pattern of cell-specific expression of cytokines and adhesion molecules that drives the brain infiltration of selected inflammatory cells;(3) CD36 expression in endothelium and microglia, not hematogenous cells, triggers the cellular and molecular events driving the component of post-ischemic inflammation that depends on CD36. We will test these hypotheses using state-of-the-art approaches for induction of transient focal cerebral ischemia with assessment of histological and behavioral outcome in mice. Flow cytometry, bone marrow chimeras and mice with cell specific inactivation of CD36 will be used to pinpoint the specific cell type(s) involved in the response.

Public Health Relevance

Stroke caused by insufficient blood flow to the brain (ischemic stroke) is a leading cause of brain damage and death, but there is a paucity of therapies to protect the brain from its devastating effects. CD36 is emerging as a critical upstream sensor and coordinator of the inflammatory reaction that plays a key role in the brain damage caused by cerebral ischemia. The proposed studies will pinpoint the specific cells expressing CD36 and will provide a therapeutic target to counter the deleterious effects of the inflammation associated with stroke.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS034179-19
Application #
8634813
Study Section
Brain Injury and Neurovascular Pathologies Study Section (BINP)
Program Officer
Bosetti, Francesca
Project Start
1995-03-20
Project End
2017-03-31
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
19
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Weill Medical College of Cornell University
Department
Neurology
Type
Schools of Medicine
DUNS #
City
New York
State
NY
Country
United States
Zip Code
10065
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