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COMPARATIVE GENOMICS OF PARASITIC NEMATODES

寄生线虫的比较基因组学

基本信息

批准号：
9285732
负责人：
Makedonka Mitreva
金额：
$ 38.07万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-23 至 2019-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9285732
关键词：
Anthelmintics Automobile Driving Basic Science Behavior Biochemical Pathway Biological Assay Buffers Communities Data Data Analyses Databases Development Diagnostic Drug Targeting Drug resistance Enzyme Inhibition Enzyme Inhibitor Drugs Enzymes Evolution Generations Genome Genomics Goals Growth and Development function Hookworms Human In Vitro Infection Intervention Intestines Laboratories Lead Maintenance Massachusetts Medical Metabolic Metabolic Pathway Metabolism Mining Molecular Monitor Morbidity - disease rate Nature Nematoda Outcome Parasite Control Parasites Parasitic nematode Parasitology Pharmaceutical Preparations Phylogenetic Analysis Post-Translational Protein Processing Poverty Predictive Value Property Proteins Protocols documentation Research Resources Sequence Analysis Structure Systems Biology Taxonomy Testing Time Universities Vaccines Validation Virulence Washington analog base burden of illness cheminformatics comparative genomics data access differential expression drug development drug sensitivity filaria human morbidity improved in vivo innovation interdisciplinary approach knowledge base medical schools metabolic abnormality assessment metabolomics molecular sequence database mortality multidisciplinary mutant novel novel diagnostics novel therapeutics parasitism pathogen pharmacophore public health priorities public health relevance reconstruction research and development tool transcriptome transcriptomics

项目摘要

DESCRIPTION (provided by applicant): Parasitic nematodes infect more than two billion people, causing significant morbidity and mortality. Characterization of the genomes of parasitic nematode provides fundamental molecular information that can be used to accelerate basic research and the development of new diagnostics and therapeutics, which are a public health priority due to the limited number of currently available drugs, the limited efficacy against some species (e.g., whipworm) and increasing anti-drug resistance. To that end, we have established an extensive genomic database by sequencing and annotating genomes and transcriptomes of nematode parasites of medical importance, including representative human parasites that span the major taxonomic clades in the phylum Nematoda. Furthermore, we focused analysis on biochemical pathways conserved and/or taxonomically restricted and condition-specific, identifying proteins that may prove useful as drug targets. The three aims of this proposal build on our progress by taking advantage of the generated multi-dimensional resource to undertake a systems biology approach aimed at promoting discovery and development of new therapeutics. First, we will reconstruct metabolic networks of both intestinal and filarial parasits, and analysis will focus on pan-conserved chokepoint enzymes in taxonomically restricted and differentially expressed metabolic pathways as potential targets for anthelmintic drugs. Second, we will perform drug-sensitivity assays to test our hypothesis and validate the predicted broad control potential of the pan-phylum targets. Third, we will perform lead optimization and demonstrate increased potency and selectivity of nematode metabolic enzyme inhibitors, followed by validation of target inhibition in vitro and in vivo. Keys to our overall approach include the selection of species of parasites that span the evolutionary extremes of the Phylum (supporting the creation of a pan-phylum metabolic pathway database with the broadest scope and optimal predictive value), the development of a prioritization protocol that leverages systems biology and cheminformatics for target and drug prioritization, followed by experimental validation and, in turn, identification and optimization of leads. The expected outcome will facilitate and promote the discovery and development of novel interventions to treat and control these important parasites and reduce their associated morbidity and mortality.