Department of Biochemistry
4-403 BSB
Iowa City, IA 52242-1109 USA phone: 877-846-8569
or 319-335-7932
fax: (319) 335-9570
biochem@uiowa.edu
Department of Biochemistry
Faculty Profiles
John E. Donelson, Ph.D.
Professor
Current Research
Our laboratory seeks to understand how gene expression is regulated in the organisms that cause the major tropical diseases of the world, such as trypanosomiasis, leishmaniasis and malaria. These parasitic organisms evade the human immune system using sophisticated molecular mechanisms that are based on the appearance of unique surface proteins at the proper times during infection. Our goal is to determine at the DNA and RNA level how these parasites developmentally regulate the production of these surface proteins in anticipation that this information will help to eliminate or better control these diseases.
One project involves a characterization of gene rearrangements that occur in African trypanosomes. These protozoan parasites are transmitted by tsetse flies to the bloodstream of humans and animals where they cause the disease trypanosomiasis or sleeping sickness. They avoid their host's immune system by periodically switching their major surface protein, a process called antigenic variation. A given trypanosome can sequentially express several hundred of these different variant surface glycoproteins (VSGs) as it continually escapes the antibodies directed against it. We have isolated the genes for several VSGs and demonstrated that gene duplications often govern the selection of a specific VSG gene to be transcribed while excluding all of the other VSG genes from expression. The expressed, duplicated gene is always located near a chromosomal telomere. We are studying the promoters that are located within these telomere-linked VSG gene expression sites, and examining possible mechanisms responsible for the high rate of mutation that we detect within some duplicated, expressed VSG genes.
Another African trypanosome project involves a 453-amino acid cytoskeletal protein that we have named trypanin. Trypanosomes have a highly polarized microtubule-based cytoskeleton with unique properties that make it an attractive target for new anti-trypanosomal drugs. When mutations are introduced into trypanin, the mutated protein localizes in different cellular regions. When expression of trypanin is knocked out by double stranded RNA interference (dsRNAi), the trypanosomes have a severe motility defect. Thus, trypanin is crucial for trypanosome viability, a property we are exploiting to better understand the mechanisms responsible for its movement.
A third project focuses on the genes for a protease, called glycoprotein 63 or GP63, that is on the surface of Leishmania chagasi, parasites which cause visceral leishmaniasis in many tropical areas. These protozoan organisms avoid their host's immune response by invading macrophages - the very cells of the immune system designed to destroy foreign pathogens. GP63 participates in the parasite's invasion of macrophages and contributes to its survival within the macrophage. We have found Leishmania actually has three different forms of GP63 that are expressed at different stages in its life cycle and probably serve different functions. The different GP63 forms are encoded by related genes that are regulated post-transcriptionally, i.e., after the initial precursor RNA is synthesized. We are now using DNA transfection procedures to examine the molecular mechanisms of this post-transcriptional and translational control of the different GP63 genes.
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