Graham Warren, professor of cell biology, and his colleagues at Yale study Trypanosoma brucei, the parasite that causes Sleeping Sickness. Like many parasites, it is exceptionally streamlined and has only one of each internal organelle, making it ideal for studying processes of more complex organisms that have many copies in each cell.
When thinking about how cells divide, doubling and separating DNA in chromosomes is often the focus. Equally important is the way a cell prepares its internal organelles for distribution. Warren studies the Golgi complex, a membrane compartment in the cytoplasm that delivers newly-made proteins to different membranes in the cell.
"Basal bodies in particular and centrosomes in general have been implicated in the biogenesis of a number of membrane-bound organelles," said Warren. "It prompted us to study further their role in Golgi duplication."
Warren's group has identified a new cellular structure, distinct from the basal body, involved in the duplication of the Golgi apparatus and defined by a highly-conserved protein, Centrin2. This structure has two lobes -- one at the old Golgi, the other where the new Golgi forms. Once a new Golgi has grown, the Centrin structure itself duplicates so that two complete structures, and associated Golgi, are ready to be allocated to daughter cells.
Significant recent advances in the molecular genetics of trypanosomes by Elisabetta Ullu and Christian Tschudi's group at Yale, allowed direct manipulation of protein levels using the innate RNA interference (RNAi) system.The relationship between the growing Golgi, the Centrin proteins and other cellular organelles was shown in experiments using RNAi, and visualizing the process was possible with fluorescent protein tags. How this process relates to higher organisms is the focus of present research.
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The work is part of the effort to unravel a number of the mysteries of lupus: Why does it occur in one identical twin and usually not the other, though they have exactly the same DNA? Why does lupus strike predominantly women? Why does it abruptly strike some while they are still young, others in middle age and others not until old age?
Mishra said the proteins expressed through the histones vary between healthy individuals and lupus patients. There also is variation among lupus patients. These differences may explain why some lupus patients develop kidney disease and others do not, or other symptoms like arthritis or skin disorders.
Prior to this research, the prevailing theory is that the variations were due to differences in genetic background and the influences of the environment. Mishra's mouse models are all genetically identical, yet variations exist. "They are the same, but different," he said. Histone changes could explain these differences. Mishra said that in addition to the use of HDAC inhibitors, combination treatment for lupus might also include a methylase inhibitor. But those don't exist yet.
Lupus is a chronic inflammatory autoimmune disorder that affects the skin, kidneys, joints, lungs, blood and central nervous system. Systemic lupus affects more than 1 million Americans, mostly women.
Mishra's coauthors are Benjamin A. Garcia, Ph.D., Scott A. Busby, Ph.D., Jeffrey Shabanowitz, Ph.D., and Donald F. Hunt, Ph.D., of the University of Virginia, Charlottesville.
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