Makedonka Mitreva, PhD
Assistant Professor of Medicine
Dr. Makedonka Mitreva joined Washington University School of Medicine in 2002 and currently serves as Assistant Professor of Medicine and Genetics. In addition to her faculty appointments, Dr. Mitreva is Assistant Director of The Genome Institute, which is one of only three NIH funded large-scale sequencing centers in the United States. Dr. Mitreva received B.S. and M.S. degrees from Ss. Cyril and Methodius University in Skopje, Macedonia and a Ph.D. from Wageningen University RC in The Netherlands. Dr. Mitreva joined the faculty after completing a post-doc at the Genome Institute, Washington University School of Medicine in St. Louis. Dr. Mitreva’s current research takes advantage of next-generation genomic and computational approaches to empower the study of infectious diseases and the human microbiome.
There are two main threads to my current research. The continued development of molecular information, bioinformatics tools, and reagents for the study of parasitic infections is crucial, therefore I continue to take advantage of next-generation technologies and implement comparative genomics approaches to study the biology and cellular pathways of these important parasites. The second area of my research is focused on the human microbiome. The approaches I am undertaking in these two areas have the potential for significant impact due to the recent explosion in the amount of data requiring analysis. The summary of my current research is provided below.
1. Apply interdisciplinary research to study pathogens of global importance. The challenges to improve control of human parasitic infections (e.g. helminths) are multi-fold and no single category of information will meet them all. New information can strengthen basic and applied biological research aimed at developing improvements. My mission is through integrated approaches and use of high-throughput techniques and comparative analysis to accelerate progress towards developing more efficient and sustainable control programs against various pathogens. For example, i) Taxonomically restricted and differentially represented pathways in helminth parasites. Some parasites undergo reductive evolution, relying on host metabolism and homeostatic buffering. Many parasitic nematodes, however, spend time outside the hosts, or have multiple hosts, therefore they may maintain or expand metabolic and regulatory functions. My comparisons of metabolic pathways at a whole genome level suggest that many pathways are conserved within the helminths but differences are noted suggesting the existence of taxonomically and condition restricted biochemical pathways that may serve to direct drug target definition. I am implementing a strategy for aligning pathway networks that combines reaction topology and protein sequence to identify conserved pathways and complexes. Analyses focus on pathways that are conserved and/or taxonomically restricted, especially enzymes that may be useful drug targets. ii) Parasite-specific protein insertions and deletion in environmental information processing and endocrine system. Conserved essential proteins within a parasite/pathogen are more resistant to evolutionary change since compromised function may be lethal. Targeting these proteins with drugs is attractive because of their essential function but problematic because of the likelihood of target-based toxicity to the host. Recent discoveries have shown that highly homologous and essential pathogen proteins may contain potentially targetable insertions and deletions (indels) when compared to human homolog(s). Our systematic analyses of proteins bearing nematode specific indels have suggested differences in their functional context and we are investigating the proteins involved in subcategories of cellular pathways that have higher rates of parasite-specific indels. We focus on protein families conserved across the most prevalent human pathogens (i.e. essential), in particular proteins involved in the endocrine system and ion signaling pathways. A subset of proteins bearing nematode specific indels undergo detailed in-silico studies to establish an opportunity for selective binding compared to the host proteins. iii) Moving towards more applied applications, I continue to study basic molecular features of the nematode intestine that figure decisively in the survival of parasitic nematodes across diverse trophic environments.
2. Human Microbiome: My current efforts are to use shotgun sequencing of metagenomic communities of microbes to understand their biology. To study metagenomic communities through shotgun sequencing, advances in computational tools were needed therefore I develop new and improve existing computational tools that will allow precise identification and comparison of taxonomic structure and functional capability of microbial communities in a robust fashion. I collaborate with informatics companies to accelerate commonly used analyses by several orders of magnitude, so as to be able to deal with the large datasets generated by shotgun sequencing. I use the tools to identify genes, pathways, and organisms within communities and use this information to determine what is common and variant among healthy individuals that will lead towards a deeper understanding of how these organisms influence human physiology, nutrition, immunity and development. Understanding the metabolic capabilities and physiologic phenotype of the community of microbes in the human microbiota is a major challenge but can provide diagnostic and therapeutic opportunities, therefore I continue to explore the core metabolome at a functional level, and reveal how the deviations from this core are associated with different physiologic states.
Link to Medline for selected publications
Washington University School of Medicine
The Genome Institute at Washington University
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