People
Program Directors
Lee Riley, Co-Director (UC Berkeley)
Henry "Chip" Chambers, Co-Director (UCSF)
Program Committee
Wayne Getz, Environmental Science, Management and Policy
Art Reingold, School of Public Health
TBD
, Molecular and Cell Biology
Temina Madon, CEND Executive Director
Fellowship Coordination
Zilose Lyons, CEND Program Manager
Sarah Gutierrez, Grant Administration
2011 Framework Fellows
Won-Chul Lee
This research aims to develop a rapid and powerful diagnosis system for malaria, which is a very important clinical, social, and economic problem in developing and underdeveloped countries. Our team previously developed Single Cell Microchamber Array (SiCMA) and plans to apply it to malaria diagnosis. The SiCMA chip is a large-scale array of small chambers in which individual cells can be rapidly collected, isolated, and subsequently lysed to create a reaction mixture of released cytosol and detection agents. To reach the goal we have formulated the following specific aims. First, we will optimize SiCMA chips and cell-loading protocols. Second, we will test SiCMA systems for malaria diagnosis in the hematology lab at CHORI. Finally, we will perform field tests of SiCMA with the Premawardena group at University of Kelaniya in Sri Lanka.
Lina Nilsson
Our project seeks to develop an affordable and portable microscopy platform for tuberculosis detection. The fluorescent microscope is based on LED lights, making it cheap and durable. Furthermore, all image acquisition and analysis is done through a software interface. This approach enables images to be saved digitally and sent wirelessly to centralized locations for diagnosis confirmation. The project vision is to increase detection rates and disease monitoring in rural point-of-care settings in the developing world. It is a collaboration between engineers in the lab of Dr. Daniel Fletcher at UC Berkeley and medical clinicians at UCSF. Through the Vietnam National Tuberculosis Program, we are now partnering with the Hanoi Lung Hospital and the National Lung Hospital of Vietnam to evaluate and improve upon our current design.
Lisa Prach
Relatively little is known about the influence of microbial factors on transmission of drug resistant Mycobacterium tuberculosis (Mtb), particularly in high HIV burden settings. Our research aims to establish preliminary data for a future definitive study which will determine the relative pathogenicity of drug-resistant Mtb. We plan to follow longitudinally all household contacts of index TB cases identified through the Beatrice Road Infectious Disease Hospital in Harare, Zimbabwe, for secondary active disease. Household contacts will be screened at baseline, 6 and 12 months for active TB suspects.
We will use geographical information system (GIS) technology and a social gathering questionnaire to record spatial, temporal, community information regarding all cases. Index cases and culture-positive secondary cases among household contacts will be genotyped. Though this proposal is exploratory and thus inadequately powered, these analyses are expected to provide crucial preliminary data for future studies and will inform the government of the current TB burden in Zimbabwe.
Christian Wilson
This project addresses the mechanism of resistance of rifampicin in Mycobacterium tuberculosis RNA polymerase (MtbRNAP) at the single molecule level. Previous research has shown that many rifampicin resistant versions of RNA polymerase remain catalytically competent, however many display altered transcriptions rates, altered pausing propensities, error prone termination efficiently, etc... These mutations have to date only been studied at the single molecule level in model organisms, such as E. coli and B. subtillis. This is an ongoing collaborative project between the laboratory of the University Cayetano Heredia in Peru and the University of California, Berkeley (UCB). We will adapt and implement the UCB-originated protocols and expertise to study the MtbRNAP and its rifampicin resistant mutants, in Peru using clinical isolates of M. tuberculosis.
2010 Framework Fellows
Olivera Marjanovic
Mce1R of Mycobacterium tuberculosis is a negative regulator of the mce1 operon whose gene products localizes to the bacterial cell wall and as such may alter overall cell wall permeability. The disruption of the mce1R leads to a hypervirulent phenotype in our mouse model of infection. Furthermore, a recent study showed that Mycobacterium tuberculosis mce1R gene harbors distinct polymorphisms that seem to be associated with increased virulence in murine models of infection. In this study we set out to analyze the mce1R gene in Mycobacterium tuberculosis clinical isolates circulating throughout New Delhi, India. The objective of our study was to determine whether we could identify a correlation between the mce1R gene sequences and the virulence of the circulating strains based on their drug susceptibility profiles. We found distinct polymorphisms in the mce1R gene in 7/10 isolates tested. Furthermore, the mce1R polymorphism containing isolates seem to cluster with their respective genotypes. We are now waiting drug susceptibility profiles of these isolates to determine a possible correlation between the drug susceptibility and the polymorphisms found in
the mce1R gene.
Seung-min Park
Elevated levels of five phospholipids in patient serum have recently been discovered by the Lee Riley Lab, the most abundant of which are cardiolipin and phosphatidylcholine. Therefore, it is hypothesized that anti-phospholipid antibodies may act as a biomarker potentially capable of indicating TB pathogenic load through the course of drug administration (Goodridge, et al. unpublished). Through collaboration with the Riley Lab, we are developing a lateral flow assay (LFA) that can be fabricated in-house very cheaply to monitor anti-phospholipid antibody levels, specifically anti-cardiolipin IgM.
Benjamin Swarts
Ethambutol (EMB) is a first-line drug that is used in concert with other antibiotics to treat tuberculosis, and recent studies have shown that the rate of acquired EMB resistance is as high as 13.7% in some countries. Testing for EMB resistance is critical so that appropriate second-line treatments can be selected, but phenotypic and genetic approaches to diagnosing EMB resistance have drawbacks. To complement these traditional methods, we are developing a chemical approach to studying/diagnosing EMB resistance based on monitoring relevant mycobacterial metabolite levels. The metabolites of interest are trehalose glycolipids, which undergo changes in abundance upon treatment with EMB and some other antibiotics. The technologies developed in this project will enable fluorescence/affinity labeling and quantification of trehalose glycolipids, which has applications in studying drug resistance, imaging, and metabolomics.
Ellen Yeh
In the face of existing or developing resistance to all available anti-malarials, there is an urgent need for the development of new therapies. We are interested in drug and vaccine development using new technologies developed by ourselves and our international collaborators in Thailand. In particular, we are focused on discovery of drugs that target the unusual plastid organelle, the apicoplast, in Plasmodium and identifying drug resistance markers.