Knowledge Generation

Francisco Diaz of Pennsylvania State University in the U.S. will develop a high-throughput screening method to identify compounds that can block two biological events essential for female fertility without affecting ovulation or hormone production in order to identify new contraceptives with fewer side effects. These two events, which occur at the same time, are cumulus expansion, whereby cumulus cells release from the oocyte to enable it to enter the oviduct, and oocyte maturation, whereby the oocyte divides to produce the egg and a smaller polar body.

Carl Nathan, Julien Vaubourgeix and Gang Lin of Weill Cornell Medical College will test their hypothesis that tuberculosis is able to exit latency by distributing damaged proteins to a senescent cell lineage, while more functional proteins are diverted to a lineage with full replication potential. Regulating this post-latency cell division could be the target of new drugs. This project's Phase I research demonstrated that M. tuberculosis accumulates irreversibly oxidized proteins when its replication is blocked. These proteins form small aggregates that fuse into larger ones.

Joseph Turner of the Liverpool School of Tropical Medicine in the United Kingdom will develop a small animal model of the parasitic disease onchocerciasis, also called river blindness, which is the second leading infectious cause of blindness. Treatment options for filarial infections are currently limited and lack effectiveness. Thus, small animal models of filarial infections are invaluable for preclinical testing of candidate drugs.

Sean Moore and colleagues at Cincinnati Children's Hospital in the U.S. will generate a mouse model of human environmental enteropathy, which is characterized by stunted growth and physiological defects in the gut, and is caused by malnutrition and repeated infections. The model will be used to test whether environmental enteropathy is affected by diet and contaminated water, and whether it reduces the effect of oral vaccines. In Phase I, they proved that feeding mice a nutritionally deficient diet mimicked at least some of the features of the human disease.

Laura Woollett of the University of Cincinnati in the U.S., in collaboration with the MRC International Nutrition Group in The Gambia, will test whether increasing plasma cholesterol in pregnant mothers from developing countries can improve fetal growth rates and reduce the associated risk of mortality and developmental defects. They hypothesized that the high incidence of low birth weight in developing countries is caused by lower levels of cholesterol in pregnant women.

Kyu Rhee of Weill Cornell Medical College in the U.S. will test the theory that the tuberculosis (TB) bacterium uses protein-based structures termed metabolosomes to enter into, maintain, and exit from latency or non-replication. Understanding how metabolosomes work will aid in development of drugs that target TB. This project's Phase I research demonstrated that latent or non-replicating M. tuberculosis undergo a metabolic remodeling that is accompanied by the reversible formation of enzyme-based metabolosomes.

Philana Ling Lin of the University of Pittsburgh in the U.S. will use imaging technologies such as PET and CT scans to study the biological mechanisms related to the reactivation of latent tuberculosis to better understand the fundamental characteristics of reactivation, as well as provide insight about new ways to induce or limit reactivation of latent tuberculosis.

Kyu Rhee of Weill Cornell Medical College in the U.S. will test the theory that tuberculosis utilizes metabolosomes, which are protein-based metabolic structures, to enter into, maintain, and exit from latency. Understanding how metabolosomes work will aid in development of drugs that target TB.

Carl Nathan and Gang Lin of Weill Cornell Medical College will test their hypothesis that tuberculosis is able to exit latency by distributing damaged proteins to a senescent cell lineage, while more functional proteins are diverted to a lineage with full replication potential. Regulating this post-latency cell division could be the target of novel drug therapies.

In the developing world, major gaps in methods and technologies to measure health status make it difficult to address inequities in health through changes in policy. Dr. Murray is leading an international team of investigators that is working to develop new technologies and methods for assessing health status in the developing world. Combining epidemiology, biomedical research, and population health assessment, the team hopes to produce new measurement tools that are science-based, standardized, and applicable to different resource-poor settings.