Nearly 80% of African children who die of malaria die of cerebral malaria (CM). The unifying pathological feature in malaria pathogenesis is the sequestration of parasitized erythrocytes in the microvasculature of various organs, including the brain. However, attempts to identify the pathogenetic mechanisms of CM have been thwarted by imprecise clinical definitions and the inability to subject relevant clinical samples t in-depth cellular and molecular biological analyses. In a significant clinical advance, the Malawi-based Blantyre Malaria Project recently identified raised intracranial pressure associated with massively increased brain volume as the clinical feature most strongly associated with death in children with stringently defined CM. While evidence of generalized endothelial dysfunction is ubiquitous in children with CM, the potential etiologies of brain swelling, e.g., vasogenic edema (blood-brain-barrier breakdown); cytotoxic edema (anoxia secondary to impaired blood flow); hyperemia (increased blood flow in response to fevers, anemia and seizures); and vascular congestion (the result of impaired venous drainage), remain poorly defined. This proposal seeks to elucidate the cellular and molecular mechanisms of cerebral vascular endothelial dysfunction that are responsible for CM mortality. It represents a synergistic, collaborative effort between clinical investigators in the Blantyre Malaria Project (University of Malawi College of Medicine, Michigan State University), and investigators in the Center for Excellence in Vascular Biology at the Brigham and Women's Hospital, Harvard Medical School where the phenomenon of endothelial dysfunction has been extensively studied. Our central hypothesis is that endothelial cell dysfunction is a pathogenetic link between the defining histological feature of CM, cytoadherence of parasitized red blood cells to brain microvascular endothelial cells (BMVEC), and the predominant clinical feature, massively increased brain volume. To test this hypothesis, Specific Aim 1 will provide annotated biological samples (archived and prospectively collected) from clinically well-characterized patients;
Specific Aim 2 will assess the effects on key endothelial functions (e.g., proinflammatory activation, increased permeability), triggered by samples from selected CM patients, in a human BMVEC-astrocyte co-culture model;
and Specific Aim 3 will define and progressively validate differentially regulated, genome-wide, human BMVEC transcriptional programs that correlate with clinical disease. Taken together, these collaborative efforts should provide a better understanding of CM pathophysiology, and identify novel therapeutic targets for adjunct therapies, and candidate biomarkers-thus advancing the goal of ending pediatric CM mortality in Africa.

Public Health Relevance

The proposed research is relevant to public health because it addresses cerebral malaria in children, a major cause of morbidity and mortality in sub-Saharan Africa. We now know that among children with cerebral malaria, those with very swollen brains are most likely to die. Our research team has expertise both in malaria and in vascular biology; our scientific approach will use samples from children with cerebral malaria and analyze them using well-established techniques in order to illuminate both the causes and potential treatments for a major scourge, falciparum malaria. (End of Abstract)

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL130624-01
Application #
9016929
Study Section
Special Emphasis Panel (ZHL1-CSR-Q (S1))
Program Officer
Hanspal, Manjit
Project Start
2015-09-15
Project End
2019-06-30
Budget Start
2015-09-15
Budget End
2016-06-30
Support Year
1
Fiscal Year
2015
Total Cost
$480,145
Indirect Cost
$56,316
Name
Michigan State University
Department
Internal Medicine/Medicine
Type
Schools of Osteopathic Medicine
DUNS #
193247145
City
East Lansing
State
MI
Country
United States
Zip Code
48824
Gimbrone Jr, Michael A; García-Cardeña, Guillermo (2016) Endothelial Cell Dysfunction and the Pathobiology of Atherosclerosis. Circ Res 118:620-36