UCR

Institute for Integrative Genome Biology



Members


Karine Le RochKarine G. Le Roch

Associate Professor

Mailing Address:

Cell Biology and Neuroscience
Genomics Building /2121B 
University of California  
Riverside, CA  92521

Phone: (951) 827-5422
Email: karine.leroch@ucr.edu

Lab Website

Degree(s):

PhD 2001 University of Oxford, U.K., University of Paris VI, France
MS 1997 University of Lille II, France BA
1995 University of Paris VI, France

College/Division Affiliation:

College of Natural and Agricultural Sciences

Center/Inst Affiliation(s):

Center for Plant Cell Biology
Center for Disease Vector Research

Areas Of Expertise:

Functional Genomics of Human Malaria Parasite, Plasmodium falciparum; Transcriptional Profiling; Cell Cycle Progression; Kinases and Ubiquitin/Proteasome Pathway; Interactome of P. falciparum; Drug Discovery Against the Malaria Parasite

Research Summary:

With an estimated 700,000 new infections each year and a child dying every 30 seconds, malaria represents one of the four most important diseases in the developing world. The absence of vaccines and the development of parasite resistance to commonly used antimalarial drugs underscores the urgency for new therapeutic approaches. The goal of my research is to define a new critical target system.  By employing genomic tools to dissect and comprehend the malaria life cycle as well as developing and utilizing drug screening assays in the context of the P. falciparumparasite, I expect to uncover new antimalarials.

Malaria Malaria is responsible for 2.7 million deaths per year making it one of the most deadly infectious diseases in the world. Transmitted by the female mosquito, Anopheles, the disease is caused by a protozoan Apicomplexan parasite, Plasmodium. Four species can infect human; P. falciparum; P. Vivax; P. malaria, and P. Ovale; P. falciparum being responsible for 95% of the case of death.   The social and economic impact at both individual and governmental levels, the absence of vaccines and the spread of parasite resistance to commonly used and inexpensive antimalarial drugs hastens the need for new therapeutic approaches.   One of the factors limiting the successful development of new antimalarials is our limited understanding of the parasite’s complex biology.

Life cycle of the malaria parasite:  Infective sporozoites enter the bloodstream from the saliva of a female anopheles mosquito and quickly invade liver cells. After 7 to 10 days, merozoites are released into the bloodstream where they invade circulating red blood cells. Parasites mature in 48 hours to produce 16 to 32 new daughter cells and are released to infect new red blood cells. The pernicious process continues until recovery or death. Following exposure to stress, parasites undergo a different developmental pathway to form sexually mature female and male gametocytes. When a mosquito takes a blood meal from an infected individual, gametocytes are ingested and sexual reproduction starts in the mosquito midgut. After maturation and multiplication, the infected mosquito transmits the disease when biting another human host.

 

Malaria in the Post Genomic Era In recent years the entire genomes of several Plasmodium species marked a significant breakthrough in the fight against the disease and allow a profound investigation of the parasite biology and its complex parasite life cycle’s regulation. Following the first publication of the genome sequences, high-throughput approaches provided the opportunity to advance our basic understanding of the Plasmodium Biology and changed the landscape of malaria research. Indeed, DNA micro-array and mass spectrometry technologies have been used to systematically characterize transcript and protein patterns across the malaria life cycle which provide important clues regarding the developmental events and their biological significance. However, the mechanisms underlying transcripts and proteins levels in the malaria parasite are still poorly understood and appear to be unconventional compared to those of most model organisms.

Taken together, these observations accentuate the need for a comprehensive biological understanding of a complex regulatory network for this unusual organism. In the process of fulfilling this task, one of the first steps is to catalog and investigate both P. falciparum proteome-wide interactions as well as post-transcriptional and post-translational modifications during key life cycle stages. Understanding the ubiquitin/proteosome system (UPS) 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.
UPS in Eukaryotic cells. The system involves the labeling of the target proteins with a small 76 amino-acids regulatory protein, ubiquitin, via a cascade of three enzymes termed E1, E2 and E3. The ubiquitin activating enzyme E1 activates the ubiquitin in an ATP dependent manner and transfers it via a thioester intermediate to an ubiquitin-conjugating enzyme, E2. Activated E2 acts with an ubiquitin ligase, E3, to transfer ubiquitin to the target substrate, forming an isopeptide bond. E3 ensures the specific recognition of the target. Then, the so ubiquitinated target can be directed through the proteasome pathway, or it can be involved in other regulations in a proteasome-independent manner.

 

Today, my laboratory is undertaking a multi pronged effort to identify components and key mechanisms of the UPS in the malaria parasite, P. falciparum.  We are employing the power of comparative genomics to discover unique apicomplexan proteins while utilizing advanced proteomic techniques to analyze the function and identify molecular interactions in the parasitic UPS pathway.  Ultimately, our main goal is to validate our genomic approach by monitoring UPS pathway activity; specifically, by using molecular genetic techniques to target disease relevant regulatory events in the parasite life cycle.

Chromatin structure and chromatin modifications Mechanisms controlling gene expression in the parasite are still poorly understood.  Rising evidence indicates that control of gene expression in P. falciparum occurs at multiple levels, one of those being chromatin remodeling. It is increasingly apparent that histone posttranslational modifications are important in chromatin structure. Physiological observations in other organisms suggest that ubiquitinated histones may have multiple functions and structural effects. Determination of chromatin's structural changes resulting from histone ubiquitination is therefore important for the understanding of transcriptional regulation within P. falciparum.  We are investigating ubiquitination of histones along the erythrocytic cycle and why these proteins are ubiquitinilated (Degradation/Activation). 
Drug discovery and natural products In addition to the fundamental scientific approach, we are developing Drug-screening assay to identify new small molecule inhibitors. Indeed screen using chemical compounds are developed in my lab using Fluorescence based assay to monitor the growth inhibition of the human malaria parasite ex vivo. An ongoing collaboration with the Scripps Oceanography Institute (San Diego, CA) is providing us with a comprehensive array of marine extracts.  Pilot tests laboratory have proved that the process have uncovered compounds that can inhibit malaria growth. Research and validation are still ongoing.
Concluding remarks With the combined efforts of target identification and small molecule and natural compound screens, we are undividedly searching for a way to break the cycle of malaria infection and resistance.

Selected Publications:

List of publications from PubMed

Lab Personnel:

Prudhomme, Jacques
Staff Research Associate —
Bol, Sebastian
Postdoctoral Researcher —
Ponts, Nadia
Postdoctoral Researcher —
Cervantes, Serena—
Graduate Student Researcher —
Chung, Doug
Graduate Student Researcher —
 

 


More Information

General Campus Information

University of California, Riverside
900 University Ave.
Riverside, CA 92521
Tel: (951) 827-1012

Career OpportunitiesUCR Libraries
Campus StatusDirections to UCR

Genomics Information

Institute of Integrative Genome Biology
2150 Batchelor Hall

Tel: (951) 827-7177
E-mail: Aurelia Espinoza, Managing Director

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