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Malaria, caused by protozoa of the genus Plasmodia, is characterized as endemic in 101 countries and annually results in 300-500 million clinical cases with over 2 million deaths worldwide. Rapid emergence of drug resistant malaria represents an ever increasing global health burden. Our research in support of efforts in combating this scourge involve multiple facets of the disease, including
- Minimizing neurological side effects of existing/under development drugs
- Enabling development of new therapeutics from natural products
- Understanding fundamental processes in host-pathogen relationship, in particular hemozoin aggregation
The CFDRC efforts in this area are briefly described below:
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Roche Molecular Diagnostic Chip (copyright) |
Pathway Model Generated From Microarray Data |
Molecular Diagnostic for Mefloquine Neurotoxicity
We have applied our integrative biological pathway-centered approach to the specific problem of identifying a genetic cause for individuals predisposed to mefloquine neurotoxicity (sponsor: Walter Reed Army Institute of Research). Mefloquine (trade name LariamTM) is highly effective against drug-resistant malaria. However, adverse neurological effects including ataxia, mood changes have been known in select sub-populations. Microarray experiments were used to quantify the transcriptional response of cells exposed to mefloquine. The differentially expressed genes were put into a biological pathway context using Gene Ontology & KEGG databases. Subsequently, the pathway model was interrogated using a novel Boolean Dynamic technique to identify and prioritize pathways that are critical to adverse effects of Mefloquine. Further analysis of these critical pathways resulted in the identification of specific sub-cellular targets that may hold the key to mefloquine toxicity on the basis of known single nucleotide polymorphisms.
Natural Anti-Malarial Therapeutics
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Natural Product Extract Generation |
Many mainstream antimalarial drugs suffer from compliance, safety (neurotoxicity), and cost complications, coupled with the fact that many of them have been compromised as a result of the rapid onset of parasitic resistance mechanisms. Natural product extracts (see promise of artiminesin) offer tremendous possibility in the development of safe and effective anti-malarial therapeutics. In collaboration with Vanderbilt University, we are leading an effort targeting the development of a high-throughput screening platform to facilitate the discovery of lead compounds from natural product extracts (NPEs). In particular, we are developing data management and analysis tools to automate the determination of optimal lead compounds using principal component analysis from simultaneous mass spectrometry, HPLC, and UV-Vis measurements. The ability of the platform and toolkit are demonstrated in identifying, detecting and characterizing compounds present in cave organism extracts, based on their anti-malarial activity. |
