This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.
Specific Aims Malaria (P. falciparum) infects 200 to 300 million people globally and kills 2 million (mostly children) every year. 15% of fatal cases are due to cerebral malaria (CM) and other severe forms of malaria. A significant segment of CM patients die regardless of recommended treatment. A significant number of survivors develop neurological complications and cognition problems. The precise mechanisms responsible for CM induced brain damage and poor prognosis is unclear. The main hypothesis of this project is that Plasmodium apoptotic factor(s) (PAF) induce neuronal and microvascular endothelial cell apoptosis and that selectively blocking PAFmediated apoptosis will negate or significantly reduce apoptosis and CM-induced pathology. Our objective is to identify and characterize the role of PAF in CM-induced brain pathology using human brain endothelial (HBVEC), glial, and neuronal cell lines, as well as our established rodent CM model respectively. We plan to utilize genomics, proteomics, immunological methods, imaging techniques, ultrastructural analysis, and targeted gene inactivation (RNA interference, RNAi) to pursue these goals. Our long-term goal is to target PAF as a therapeutic strategy for preventing or treating CM-induced brain pathology.
Three Specific Aims have been proposed to study the role of apoptosis in CM-induced brain pathology.
Specific aim 1 will compare and contrast CM induced apoptosis in murine CM models with that in P. falciparum-induced human CM using post mortem brain tissues. CM-induced expression changes in apoptotic factors in murine and human CM will be compared by gene and protein expression analysis, ultrastructure, immunohistology, and DNA cleavage (TUNEL) analysis.
Specific aim 2 will identify and characterize the key apoptotic factor(s) (PAF) mediating CM-induced apoptosis. Gene and protein expression data (gene microarray chips, 1D & 2D gel electrophoresis) and protein Mass spectroscopy (MALDI-TOF) will be utilized to identify and characterize the potential role of PAF in CM-induced apoptosis in HBVEC, glia, and neuronal cell lines in vitro.
Specific aim 3 will functionally characterize CM-mediated apoptosis in CM. Antibody blocking procedures and, if necessary, RNA interference (RNAi) strategies will be used to knock down expression of host PAF receptor(s) in HBVEC, glial, and neuronal cell lines induced by parasite infected RBC (IRBC) and uninfected controls and assayed for apoptosis. BBB integrity will be evaluated in an in vitro BBB model in the presence or absence of IRBC. We will also exogenously block PAF with anti-PAF antibody in murine CM model and examine effects on BBB and CM pathology.

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
Research Centers in Minority Institutions Award (G12)
Project #
5G12RR003034-22
Application #
7561418
Study Section
National Center for Research Resources Initial Review Group (RIRG)
Project Start
2007-06-01
Project End
2008-05-31
Budget Start
2007-06-01
Budget End
2008-05-31
Support Year
22
Fiscal Year
2007
Total Cost
$146,540
Indirect Cost
Name
Morehouse School of Medicine
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
102005451
City
Atlanta
State
GA
Country
United States
Zip Code
30310
Owino, Sharon; Sánchez-Bretaño, Aida; Tchio, Cynthia et al. (2018) Nocturnal activation of melatonin receptor type 1 signaling modulates diurnal insulin sensitivity via regulation of PI3K activity. J Pineal Res 64:
Augello, Catherine J; Noll, Jessica M; Distel, Timothy J et al. (2018) Identification of novel blood biomarker panels to detect ischemic stroke in patients and their responsiveness to therapeutic intervention. Brain Res 1698:161-169
Greene, Sarah J (2018) The use and effectiveness of interactive progressive drawing in anatomy education. Anat Sci Educ 11:445-460
Chowdhury, Indrajit; Banerjee, Saswati; Driss, Adel et al. (2018) Curcumin attenuates proangiogenic and proinflammatory factors in human eutopic endometrial stromal cells through the NF-?B signaling pathway. J Cell Physiol :
Piano, Ilaria; Baba, Kenkichi; Claudia Gargini et al. (2018) Heteromeric MT1/MT2 melatonin receptors modulate the scotopic electroretinogram via PKC? in mice. Exp Eye Res 177:50-54
Huang, Ming-Bo; Gonzalez, Ruben R; Lillard, James et al. (2017) Secretion modification region-derived peptide blocks exosome release and mediates cell cycle arrest in breast cancer cells. Oncotarget 8:11302-11315
Sánchez-Bretaño, Aída; Baba, Kenkichi; Janjua, Uzair et al. (2017) Melatonin partially protects 661W cells from H2O2-induced death by inhibiting Fas/FasL-caspase-3. Mol Vis 23:844-852
Hu, Guoku; Yelamanchili, Sowmya; Kashanchi, Fatah et al. (2017) Proceedings of the 2017 ISEV symposium on ""HIV, NeuroHIV, drug abuse, & EVs"". J Neurovirol 23:935-940
Laurent, Virgine; Sengupta, Anamika; Sánchez-Bretaño, Aída et al. (2017) Melatonin signaling affects the timing in the daily rhythm of phagocytic activity by the retinal pigment epithelium. Exp Eye Res 165:90-95
Chowdhury, Indrajit; Branch, Alicia; Mehrabi, Sharifeh et al. (2017) Gonadotropin-Dependent Neuregulin-1 Signaling Regulates Female Rat Ovarian Granulosa Cell Survival. Endocrinology 158:3647-3660

Showing the most recent 10 out of 291 publications