User:Huayu Ding/Notebook/20.109 TR Blue

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Project Description/Abstract

Developing new biomolecules to stop malaria.



Malaria develops in two phases: an exoerythrocytic phase, where the liver is infected, and then an erythrocytic phase, where the red blood cells are infected. The body's immune system is unable to defend against the parasite because it resides within the liver and blood cells and is effectively invisible to white blood cells. The infected blood cells could be destroyed in the spleen, but the protist prevents such an outcome by displaying adhesive proteins on the surface of the infected blood cells, causing the cell to stick to the walls of the small blood vessels. This mechanism is the main cause of hemorrhage and brain damage in infected patients.

Phage Assisted Continuous Evolution (PACE)

PACE is a newly developed method of directed evolution to increase the affinity of biomolecular interactions (protein or nucleic acids). Because phage is produced at a much higher frequency than its E.coli hosts, this system is designed so that the phage carries the pool of the molecules of interest, while the E.coli participate in selection and act as the factory to produce new phage. The phage in PACE have a deleted gene III that produces protein III (pIII). PIII is required for phage infection, so for the phage vectors to continue reproducing, they have to evolve the molecule of interest to produce pIII in a plasmid on the E.coli. The binding affinity of the molecule of interest is thus directed linked to the fitness of a phage, and those with better affinity can proliferate.

Problems and Goals

Malaria affects millions of people every year in tropical regions, especially sub-saharan Africa. The disease is caused by parasites in the genus Plasmodium. Once in the bloodstream, the parasite prevents red blood cells from deforming and squeezing through capillaries causing blockages. According to a study done by a team led by MIT, a protein called Ring-infected Erythrocyte Surface Antigen (RESA) causes red blood cells to become less deformable. The goal of this project would be to generate a protein binder to this RESA protein and inhibit its activity. A recent study by Esvelt et al. describes a method for continuous directed evolution of a desired protein. The method uses system engineering and links the desired trait of interest with the production of viable phage in E. coli. Phage carrying gene variants that match the criteria are given better fitness. The products generated from this project would be tested as potential malaria treatments.

Predicted Outcomes

Resources Needed