Welcome to Le Roch Lab

Our Research

Our research focuses on developing biological and technological tools to dissect the molecular events driving the human malaria parasite life cycle progression. Using functional genomics approaches, we expect to elucidate critical regulatory networks driving the parasite life cycle and identify novel therapeutic strategies.

Revealing the parasite chromatin structure and its role in transcriptional regulation

Mechanisms controlling gene expression in the parasite are still poorly understood. Rising evidences indicate that control of gene expression in P. falciparum occurs at multiple levels, one of those being chromatin remodeling. It is increasingly apparent that histone turnover and histone post-translational modifications are important in chromatin structure and transcriptional regulation. Determination of chromatin’s structural changes will therefore be critical for the understanding of transcriptional regulation in Plasmodium. Using next generation sequencing technology and histone pull down followed by mass spectrometry analyses; we are investigating the parasite dynamic nucleosome landscapes.

Drug discovery and natural products

In addition to fundamental scientific approaches, we are developing drug-screening assays and high content live cell confocal imaging technologies to identify small molecule inhibitors and their morphological effects on the human malaria parasite. Ongoing collaborations with the Scripps Oceanography Institute (San Diego, CA) and the Georgia Institute of technology are providing us with a comprehensive array of marine extracts. So far we have already uncovered several compounds that can inhibit malaria growth in the low nano molar ranges. Experiments to identify drug targets and drug mechanism of actions are still ongoing.

Understanding the parasite ubiquitination system

One of the fundamental ways in which eukaryotic organisms regulate dynamic cellular processes is by invoking the ubiquitin/proteosome system (UPS). As a central hub for protein turnover and post-translational modification, the UPS is being showcased as an important system for therapeutic intervention in a host of human diseases.Today, the laboratory is undertaking a multi pronged effort to identify components and key mechanisms of the ubiquitination system in malaria. We are employing the power of comparative genomics to discover unique apicomplexan proteins while utilizing advanced genomics and proteomic techniques to analyze the function of parasite specific ubiquitin-ligases. Ultimately, our main goal is to target disease relevant regulatory events in the parasite life cycle.

Next-generation sequencing technology:

With the ultimate goal of deciphering the human malaria parasite genome to find new therapeutic approaches, we are using the Illumina multiplex polony sequencing technology. By sequencing sequence millions of short DNA fragments, we are unlocking the way parasites replicate inside the reed blood cells.

Mass spectrometry and multidimentional protein identification technology (MudPIT):

Based on resources created by whole genome sequencing, large-scale analyses of protein expressed at a particular time of the malaria parasite infectious cycle are now possible. Together with Dr. L Florens at the Stowers institute, we are in the process of understanding how malaria parasite proteins are regulated. Using the multidimensional protein identification technology (MudPIT), we are analyzing highly protein complex samples by liquid chromatography separation of peptides on a microcapillary column, electrospray ionization, tandem mass spectrometry (MS/MS), and database searching.

High content live cell confocal imaging:

The application of advanced techniques to high content live cell imaging using the Pathway Bioimaging System allows us to address sophisticated questions via large-scale biological screens. It is possible to observe changes in parasite morphology in response to chemical perturbations. Live cells with the use of fluorescent reporter can be queried at high spatial resolution using confocal microscopy for morphological changes. Finally, automated high content image screening can be used to identify new antimalarial drugs, their effect on the parasite and their potential mode of action. For more information about our technology