Post-ischemic inflammation complicates the development of cerebral injury triggered by ischemic stroke. CD36 is a class B scavenger receptor that has a high affinity for oxidized low-density lipoprotein (oxLDL). CD36 functions in the uptake of oxLDL and subsequent foam cell formation in aorta and may also contribute to the pro-inflammatory milieu. On the basis of proatherogenic and proinflammtory property of CD36, we hypothesize that CD36 expressed in brain functions as a primary mediator for ischemia-induced inflammation associated with cerebral injury and that CD36 is thus a target for pharmacological intervention. To test these hypotheses, Aim 1will investigate the dependency of CD36 in eliciting ischemia-induced inflammatory responses and cerebral injury using two approaches: Genetically using CD36 knock-out (KO) mice and pharmacologically using hexarelin.
Aim 2 will determine whether microglia/macrophage CD36 expression is a critical mediator for post-ischemic inflammation and cerebral injury by comparing inflammatory markers and functional outcomes in wild type (WT) and CD36 KO mice transplanted with either WT or CD36 KO hematopoietic stem cells. A role for microglia CD36 will be further studied by assessing inflammatory responses in the post-ischemic brain prior to blood brain barrier deterioration.
Aim 3 will test the clinical relevance of a pro-inflammatory role of CD36 by examining the CD36-mediated effects in a model of hypercholesterolemia. Accordingly, CD36 expression and ligand availability will be assessed in the post- ischemic brain in stroke-prone ApoE KO mice fed a high fat Western diet. In addition, we will compare inflammatory markers and functional outcomes in ApoE KO and ApoE/CD36 double KO mice fed the Western diet and also in ApoE KO mice fed the Western diet with statins, lipid lowering drugs. This proposal, in its entirety, will develop novel strategies important to ameliorating post-ischemic inflammation and cerebral injury in stroke victims. (lay version)This study aims to investigate whether CD36, a multifunctional receptor, is involved in inflammation and brain injury after an ischemic stroke. Understanding contributing roles of CD36 on brain injury will lead to potential therapeutic strategies to treat stroke patients.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL082511-05
Application #
7770869
Study Section
Special Emphasis Panel (ZHL1-CSR-H (O1))
Program Officer
Kindzelski, Andrei L
Project Start
2006-02-15
Project End
2011-08-04
Budget Start
2010-02-01
Budget End
2011-08-04
Support Year
5
Fiscal Year
2010
Total Cost
$450,844
Indirect Cost
Name
Winifred Masterson Burke Med Research Institute
Department
Type
DUNS #
780676131
City
White Plains
State
NY
Country
United States
Zip Code
10605
Banerjee, Kalpita; Munshi, Soumyabrata; Xu, Hui et al. (2016) Mild mitochondrial metabolic deficits by ?-ketoglutarate dehydrogenase inhibition cause prominent changes in intracellular autophagic signaling: Potential role in the pathobiology of Alzheimer's disease. Neurochem Int 96:32-45
Woo, Moon-Sook; Yang, Jiwon; Beltran, Cesar et al. (2016) Cell Surface CD36 Protein in Monocyte/Macrophage Contributes to Phagocytosis during the Resolution Phase of Ischemic Stroke in Mice. J Biol Chem 291:23654-23661
Kim, Eunhee; Cho, Sunghee (2016) Microglia and Monocyte-Derived Macrophages in Stroke. Neurotherapeutics 13:702-718
Kim, Eunhee; Woo, Moon-Sook; Qin, Luye et al. (2015) Daidzein Augments Cholesterol Homeostasis via ApoE to Promote Functional Recovery in Chronic Stroke. J Neurosci 35:15113-26
Kim, Eun-Hee; Tolhurst, Aaron T; Szeto, Hazel H et al. (2015) Targeting CD36-mediated inflammation reduces acute brain injury in transient, but not permanent, ischemic stroke. CNS Neurosci Ther 21:385-91
Kim, Eunhee; Yang, Jiwon; Beltran, Cesar D et al. (2014) Role of spleen-derived monocytes/macrophages in acute ischemic brain injury. J Cereb Blood Flow Metab 34:1411-9
Kim, Eunhee; Tolhurst, Aaron T; Cho, Sunghee (2014) Deregulation of inflammatory response in the diabetic condition is associated with increased ischemic brain injury. J Neuroinflammation 11:83
Qin, Luye; Jing, Deqiang; Parauda, Sarah et al. (2014) An adaptive role for BDNF Val66Met polymorphism in motor recovery in chronic stroke. J Neurosci 34:2493-502
Kim, Eunhee; Febbraio, Maria; Bao, Yi et al. (2012) CD36 in the periphery and brain synergizes in stroke injury in hyperlipidemia. Ann Neurol 71:753-64
Cho, Sunghee (2012) CD36 as a therapeutic target for endothelial dysfunction in stroke. Curr Pharm Des 18:3721-30

Showing the most recent 10 out of 20 publications