2010 Opportunities
For the 2010 Minority Health — Global Health Fellowship, you may apply to no more than two (2) of the research projects described below. Please read the descriptions carefully and ensure that you have the qualifications required to complete the project. If you have any questions, please contact the MHIRT program. Please DO NOT contact the professors directly.
BRAZIL — Phylogenomics of Protozoa
Kimmen Sjolander & Alberto Davila (2 slots)
Background: This collaboration is focused on the phylogenomics of Protozoa, a class of eukaryotic organisms that includes the parasites plasmodium, trypanosoma, and leishmania. The research is conducted through a partnership of the Sjolander lab at UC Berkeley and the IAEA Collaborating Center for Bioinformatics and Animal Genomics at Instituto Oswaldo Cruz/FIOCRUZ, led by Dr. Alberto Davila.
Project Description: The students will participate in enhancements of the ProtozoaDB database maintained by FIOCRUZ, including the population of the database with data on environmental Protozoa from genome data available in GenBank. In addition, students will be involved in: (a) reconstructing phylogenetic trees for gene families and predicting orthologs using a variety of bioinformatics methods (enabling comparisons of pathogenic protozoa with environmental species), and (b) detecting and predicting protein function and analyzing metabolic pathways in different species.
Qualifications: Linux experience, bioinformatics coursework relevant to protein function or structure prediction, and programming experience in either Perl or Python.
BRAZIL — Bacterial and Viral Infections
Lee Riley & TBD (1 slot)
Background: The Riley laboratory has been involved in collaborative projects in Brazil since 1990. The collaboration has focused on infectious diseases of importance to urban centers, specifically on infectious diseases of urban slums. Brazil has undergone more than 350% increase in its urban population since 1960. This has engendered completely new types of health problems with magnitude not seen in most developing or developed countries. Urbanization and the explosive increase in shantytown populations have created a new set of health problems: chronic infectious (TB, AIDS, post-infectious cardiovascular and renal diseases) and non-infectious diseases (hypertension, diabetes, asthma, and unintentional and unintentional injuries). A single placement with the Riley lab will be available in Brazil, but the particular project and site will be negotiated once a student joins the lab. The options are outlined below.
Possible Project 1 (Oswaldo Cruz Foundation, Salvador): Exploiting the knowledge gained from basic TB pathogenesis research conducted at UC Berkeley, we are evaluating immunological responses in patients with latent infection, to determine responses predictive of those who may progress to active disease. In addition, we are evaluating a new serologic method to monitor response to treatment in those newly diagnosed to have TB. This is done in collaboration with researchers at Oswaldo Cruz Foundation and Octavio Mangabeira Hospital in Salvador, Brazil. A second project in Salvador, also in partnership with the Oswaldo Cruz Foundation, has studied the risk factors and natural history of leptospirosis for 9 years in one favela of a population of 58,000. This collaboration led to the identification of a protein made by the bacterium that causes leptospirosis, which the Brazilian government has adopted to apply for international patent rights for use as a new highly sensitive diagnostic test. Community-based studies have also identified favela-related risk factors that the local city government has made attempts to correct.
Possible Project 2 (University of Sao Paulo): Along with the TB study being conducted in Salvador (Possible Project 1), we have been studying the transmission dynamics of TB in one large neighborhood of Sao Paulo for the last 8 years. Data generated from this prospective study, conducted in collaboration with investigators at the University of Sao Paulo and the Adolfo Lutz Institute in Sao Paulo, will be used to identify appropriate cohorts for eventual evaluation of the prognostic test outlined above.
Possible Project 3 (Federal University of Rio de Janeiro): Hospital infections are a major emerging problem in Rio de Janeiro as well as in other major cities of Brazil. For the last 4 years, we have been conducting molecular epidemiologic studies with the Federal University of Rio de Janeiro, to understand risk factors for transmission and characterize pathogens implicated in infections in a large university hospital in Rio.
Possible Project 4 (Federal University of Bahia, Salvador): A large proportion of those who undergo mitral valve replacement due to rheumatic disease come from favelas. Little is known of the factors that lead to rheumatic heart disease in these communities. Both conventional epidemiology and molecular epidemiology studies are being conducted to characterize epidemiologic as well as pathogen determinants of progression to post-infectious complications. This work is conducted in partnership with the Federal University of Bahia in Salvador, Brazil.
CHINA — HIV Transcription Activation
Qiang Zhou & Ruichuan Chen (1 slot)
Title: Functional characterization of novel Tat partners key for activation of HIV-1 transcription.
Background: We are interested in elucidating the mechanisms and identifying host cellular co-factors that control HIV-1 transcription. It was 12 years ago when the human transcription elongation factor P-TEFb was first identified as a host cofactor for activation of HIV-1 transcription by the viral encoded Tat protein. Recruited by Tat to the viral LTR, P-TEFb stimulates RNA polymerase II elongation, a process essential for viral replication. Since 1997, this landmark discovery has provided the basic framework for our understanding of Tat function during the HIV life cycle, and P-TEFb remains the only widely accepted functional Tat partner till this day. However, published data suggest that Tat-transactivation involves more than the interaction between Tat and P-TEFb. A major effort of ours is thus aimed at identifying additional cellular factors that may associate with Tat-P-TEFb to further enhance Tat-transactivation.
Project Description: Recently, our laboratory has successfully identified the first new Tat partners in more than a decade. The MHIRT research apprentice will use a combination of molecular and biochemical techniques to characterize these new factors and determine the mechanism by which they cooperate with Tat and P-TEFb to stimulate HIV-1 transcription. A portion of this project can be conducted in our collaborator's lab led by Dr. Ruichuan Chen in Xiamen University in China.
International Site: The partner site for this project is the HIV Molecular Pathology Lab in the School of Life Sciences at Xiamen University, China. The lab is led by Dr. Ruichuan Chen. Dr. Chen's lab has a demonstrated track record in conducting original and high quality research in the area of mammalian gene expression control, with a special emphasis on the mechanisms controlling HIV transcription and transcriptional control in cancer. The lab and Xiamen University have standard training and educational programs in place for international students at both the undergraduate and graduate levels. His lab is equipped with all the necessary tools and equipment that are required for conducting modern biochemical and molecular biology research. The School of Life Sciences also has many pieces of high-end equipment that are shared by all the members of the school. The visiting student will first be paired with a senior graduate student or a postdoc in the lab in order to become familiar with the daily operations in the lab. After that, the student will be assigned an independent research project and closely supervised by Dr. Ruichuan Chen on a daily basis (approximately 10% of Dr. Chen's time).
Qualifications: Advanced undergraduates or graduate students in MCB will have the appropriate background to complete this project.
Websites:
Dr. Zhou Q: http://mcb.berkeley.edu/faculty/BMB/zhouq.html
Dr. Chen R: http://life.xmu.edu.cn/teacher/HTML/982.html
CHINA — HIV & Prostratin
Qiang Zhou & Ruichuan Chen (1 slot)
Title: The mechanism of Prostratin activation of HIV-1 transcription
Background: Despite the fact that Highly Active Antiretroviral Therapy (HAART) can significantly reduce the HIV virus load in the blood, infected patients still harbor approximately 105—106 memory CD4+ T-cells that contain fully integrated but transcriptionally silent HIV proviruses. While small in number, these latently infected cells form the drug-insensitive reservoir that contributes to the life-long persistence of HIV infection. How to eradicate this latent HIV pool has been a major challenge facing the entire HIV field. One attractive strategy is to activate the transcription of latent proviruses present in infected quiescent T-cells, which can then be killed by HAART.
Project Description: The goal of this project is to investigate how Prostratin, a potential anti-HIV latency drug, activates HIV-1 transcription. Emphasis is placed on the identification of cellular signaling pathway(s) that are essential for mediating the stimulatory effect of Prostratin on HIV-1 transcription. The research will focus on members of the protein kinase PKC and PKD families as potentially important for Prostratin activation of HIV-1 transcription. The MHIRT student will use a combination of molecular biology and biochemistry techniques to identify the signaling pathway(s) involved in Prostratin stimulation of HIV-1 transcription. The project will be conducted initially in Dr. Qiang Zhou's laboratory at UCB and then in our collaborator, Prof. Ruichuan Chen's laboratory at Xiamen University in China.
International Site: The partner site for this project is the HIV Molecular Pathology Lab in the School of Life Sciences at Xiamen University, China. The lab is led by Dr. Ruichuan Chen. Dr. Chen's lab has a demonstrated track record in conducting original and high quality research in the area of mammalian gene expression control, with a special emphasis on the mechanisms controlling HIV transcription and transcriptional control in cancer. The lab and Xiamen University have standard training and educational programs in place for international students at both the undergraduate and graduate levels. His lab is equipped with all the necessary tools and equipment that are required for conducting modern biochemical and molecular biology research. The School of Life Sciences also has many pieces of high-end equipment that are shared by all the members of the school. The visiting student will first be paired with a senior graduate student or a postdoc in the lab in order to become familiar with the daily operations in the lab. After that, the student will be assigned an independent research project and closely supervised by Dr. Ruichuan Chen on a daily basis (approximately 10% of Dr. Chen's time).
Qualifications: Advanced undergraduates or graduate students in MCB will have the appropriate background to complete this project.
Websites:
Dr. Zhou Q: http://mcb.berkeley.edu/faculty/BMB/zhouq.html
Dr. Chen R: http://life.xmu.edu.cn/teacher/HTML/982.html
INDIA — TB Drug Discovery
TBD & Satyahari Dey (1 slot)
Background: Approximately one third of the world's population is infected with tuberculosis (TB), a disease that affects 50,000 persons each week. A grave public health concern is the increase of HIV-associated TB, as well as the emergence of MDR (Multiple Drug Resistant) and XDR (Extremely Drug Resistant) strains of Mycobacterium tuberculosis, the causative pathogen. The genome sequence of M. tuberculosis has now been deciphered, and nearly 4,000 genes identified. Most have been annotated as secretory, cytosolic, cell wall and cell membrane-associated, metabolic, respiratory, and virulence proteins. This project is conducted through a partnership with two labs at the Indian Institute of Technology, Kharagpur campus.
Project Description: The project has two components, both in the area of M. tb drug discovery and each lasting 4 weeks. The first project focuses on a bacterial protein encoded by the gene Rv3922c. The protein is a possible hemolysin bearing similarity to alpha hemolysin from Aeromonas hydrophila. The A. hydrophila alpha hemolysin of has the capability to lyse fish blood cells. The putative hemolysin from M. tb has a domain of unknown function and is non-secretory in nature. It has been cloned in pQE30 vector and successfully expressed, solubilized and purified. A characterization of this protein will be carried in the lab of Prof. A.K. Das in India, involving optimization of the protein's crystallization, data collection for the crystals obtained, heavy atom derivatization of crystals, and characterization of the purified protein by hemolysis assay and by different spectroscopic means. The second component of the project involves screening of phenolic & terpenoid anti-microbial metabolites against Mycobacteium smegmatis. The proposed small molecules from two plant sources (Santalum album and Vitex negundo) will be isolated and characterized. The molecules will then be tested for their anti-microbial activities using M. smegmatis as test organism. The major steps in the project are isolation of the metabolites from plant material by solvent extraction and chromatographic techniques, characterization of one or two major metabolites by mass spectrometry, and anti-microbial assay using Minimum Inhibitory Concentration (MIC) and related methods.
INDIA — Bacterial and Viral Infections
Lee Riley & TBD (1 slot)
Background: The Riley laboratory has been involved in collaborative projects in India since 2007. There will be one fellowship available in India, in one of 2 possible locations. The final placement in India will be negotiated once a student joins the Riley lab.
Possible Project 1 (Mahatma Gandhi Institute, Sevagram): This collaboration is centered at the Mahatma Gandhi Institute of Medical Sciences, the first rural medical college of India, in the village of Sevagram. The collaborator is Dr. SP Kalantri. The research focuses on 1) the application of diagnostic and prognostic tests for TB, in a clinic/hospital setting (for example, evaluating diagnostic tests for sensitivity and reliability); and 2) descriptive and laboratory studies to characterize viral epidemics in Sevagram. For the latter project, we are conducting further research to understand the large epidemic of febrile illness (of unknown etiology) that residents of Sevagram experience each year. In summer of 2006, the epidemic was characterized by fever and arthralgia, and was suspected to be caused by Chikungunya virus.
Possible Project 2 (Public Health Research Institute, Mysore): Women residents of slums have a high incidence of bacterial vaginosis (BV), which is associated with adverse birth outcomes. A project examining the epidemiology and biology of BV has been initiated in a slum population of Mysore, India, done in collaboration with Dr. Purnima Madhivanan of the Public Health Research Institute in Mysore, India. It includes studies of the sensitivity and reliability of diagnostic tests for BV, as well as laboratory analyses of patient samples.
UGANDA — Malaria Drug Trials
Philip Rosenthal & Moses Kamya (1+ slots)
Background: Our group performs clinical and translational research on malaria and malaria/HIV in Africa and at UCSF. The team at UCSF includes Grant Dorsey, Sunil Parikh, and Bryan Greenhouse (Division of Infectious Diseases, Dept. of Medicine, UCSF) along with collaborators at Makerere University. The ongoing collaboration is formally known as the Makerere University-UCSF Uganda Malaria Research Program. There is possibility for a placement in Uganda, where most of our operations are headquartered; however, the fellow may have an opportunity to work in Burkina Faso as well.
Project Description: Clinical trials in Uganda are examining the efficacy of different drug regimens for the treatment or prevention of malaria and the antimalarial effects of antiretroviral drugs. Translational studies related to these trials offer potential opportunities for students. Topics may include clinical, epidemiology, or molecular research. In particular, we are interested in predictors of and mechanisms of drug resistance. Other studies in Uganda involve surveillance of malaria at rural clinics across the country. Studies in Burkina Faso may involve evaluations of antimalarial drug efficacy and resistance.
Qualifications: Students studying biology or public health are preferred.
Website: Additional information on our projects is available at http://www.muucsf.org.
UGANDA — TB Quroum Sensing Genes
Tom Alber & Moses Joloba (2 slots)
Title: Functional Characterization of Quorum Sensing homologues in mycobacteria
Background: This project involves studying homologues of quorum sensing genes in mycobacteria. Pathogenic mycobacteria cause life-threatening diseases such as tuberculosis (TB), Buluri ulcer, leprosy and opportunistic infections. Cell-to-cell signaling (bacterial quorum sensing) is a cell density dependent gene regulation mechanism that occurs in most bacteria and regulates most of bacterial physiological processes, including sporulation, biofilm formation, production of antibiotics, etc. In some pathogenic bacteria such as pseudomonas, staphylococcus virulence and pathogenesis are determined by quorum sensing. Quorum sensing has not yet been demonstrated in mycobacteria, but homologues of quorum sensing genes occur in genomes of sequenced mycobacteria.
Project Description: The MHIRT research apprentices will use molecular techniques as well as microbiological techniques to help us genetically characterize quorum sensing genes in mycobacteria. The apprentices will construct mycobacteria suicide vectors, transform mycobacteria, and analyze mutants of quorum sensing homologues. The apprentices will also a) analyze the ability of mutants to multiply in macrophage and mice; b) participate in creation and characterization of quorum sensing gene regulated fusions in Mycobacterium smegmatis using a newly constructed delivery vector special for mycobacteria. The study of quorum sensing homologues in mycobacteria will help clarify their role(s) in the physiology of mycobacteria, their role(s) in virulence and pathogenesis.
International Site: The partner site for this project is the Makerere University College of Health Sciences in Kampala, Uganda. The host lab is Medical & Molecular Laboratories, led by Dr. Moses L. Joloba, head of the department of Medical Microbiology. Dr. Joloba has obtained a grant from NIH studying "Cell to Cell signaling in Mycobacteria". The lab has introduced PCR detection and DNA fingerprinting techniques for M. tuberculosis as a routine for Ugandan research labs and health workers. The laboratory has 7 PhD students and 4 MS students.
Qualifications: Coursework in biochemistry, microbiology, cell biology.
Website: http://www.mbl.mak.ac.ug/