More than 1 million children die from malaria in sub-Saharan Africa each year, and in areas along the Thailand/Cambodian border multiple drug-resistant strains of the disease are becoming commonplace.
With the previously mainstay antimalarial drug chloroquine nearly ineffective due to drug resistance and traditional public health approaches such as mosquito netting offering uneven results, two new papers by University of Notre Dame biologist Michael Ferdig suggest that the means of combating this old foe may lie in the new tools of genomics and bioinformatics.
In the papers, Ferdig points out that development of the malaria parasite Plasmodium falciparum in the blood is driven by a number of different genes expressed at different times and at different levels. Exactly what influences such transcriptional changes remains elusive, particularly in regard to important phenotypes like drug resistance.
Ferdig and his collaborators combined classical genetics with cutting-edge genomic methods to illuminate previously unrecognized transcriptional complexity and variation in Plasmodium falciparum and possibly master regulators within large copy number variants that contribute to the drug-resistant phenomena in malaria parasites.
By uncovering the genetic "architecture" of numerous drug responses and identifying key regulators that control these responses, Ferdig hopes to map new approaches to conquering drug resistant malarial genes.
One paper from the Ferdig lab appeared in the journal PLoS Biology. The second, in collaboration with Tim Anderson at Southwest Biomedical Research Foundation, appeared in PLoS Genetics .
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In fact, many of these haplessly activated genes are directly linked with aging phenotypes. The researchers found that a number of such unregulated mouse genes were persistently active in older mice.
"We then began wondering what would happen if we put more of the sirtuin back into the mice," says Oberdoerffer. "Our hypothesis was that with more sirtuins, DNA repair would be more efficient, and the mouse would maintain a youthful pattern gene expression into old age."
That's precisely what happened. Using a mouse genetically altered to model lymphoma, Oberdoerffer administered extra copies of the sirtuin gene, or fed them the sirtuin activator resveratrol, which in turn extended their mean lifespan by 24 to 46 percent.
"It is remarkable that an aging mechanism found in yeast a decade ago, in which sirtuins redistribute with damage or aging, is also applicable to mammals," says Leonard Guarente, Novartis Professor of Biology at MIT, who is not an author on the paper. "This should lead to new approaches to protect cells against the ravages of aging by finding drugs that can stabilize this redistribution of sirtuins over time."
Both Sinclair and Oberdoerffer agree with Guarente's sentiment that these findings may have therapeutic relevance.
"According to this specific mechanism, while DNA damage exacerbates aging, the actual cause is not the DNA damage itself but the lack of gene regulation that results," says Oberdoerffer. "Lots of research has shown that this particular process of regulating gene activity, otherwise known as epigenetics, can be reversed ”unlike actual mutations in DNA. We see here, through a proof-of-principal demonstration, that elements of aging can be reversed."
Recent findings by Chu-Xia Deng of the National Institute of Diabetes, Digestive and Kidney Diseases, has also found that mice that lack sirtuin are susceptible to DNA damage and cancer, reinforcing Sinclair's and Oberdoerffer's data.
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