Abstract
ABSTRACTRapamycin and other mTOR inhibitors are being heralded as possible treatments for many human ailments. It is currently being utilized clinically as an immunomodulator after transplantation procedures and as a treatment for certain forms of cancer, but it has numerous potential clinical indications. Some studies have shown profound effects on life cycle and muscle physiology, but these issues have not been addressed in an organism undergoing developmental processes. This paper fills this void by examining the effect of mTOR inhibition by rapamycin on several different qualities of larval Drosophila. Various dosages of the compound were fed to second instar larvae. These larvae were monitored for pupae formation to elucidate possible life cycle effects, and a delay to pupation was quantified. Behavioral deficits were documented in rapamycin-treated larvae. Electrophysiological measurements were taken to discern changes in muscle physiology and synaptic signaling (i.e. resting membrane potential, amplitude of excitatory post-synaptic potentials, synaptic facilitation). Pupation delay and effects on behavior that are likely due to synaptic alterations within the central nervous system were discovered in rapamycin-fed larvae. These results allow for several conclusions as to how mTOR inhibition by rapamycin affects a developing organism. This could eventually allow for a more informed decision when using rapamycin and other mTOR inhibitors to treat human diseases, especially in children and adolescents, to account for known side effects.
Highlights
Regulating growth and division is an important feature of all cells, both within unicellular and multicellular organisms
The mTOR pathway has been found to be highly conserved in a variety of organisms and rapamycin has consistently been effective at inhibiting mTOR (Jacinto and Hall, 2003)
Life cycle quantification Data from the life cycle quantification aspect of the project consisted of a proportion of larvae that pupated over time
Summary
Regulating growth and division is an important feature of all cells, both within unicellular and multicellular organisms. Cells have multiple biochemical systems that regulate the process. One such system is the mTOR (mechanistic target of rapamycin). Subsequent studies in other organisms, yeast, found that rapamycin prevented progression through the cell cycle. This led to the discovery of the mTOR nutrient-sensing pathway and its role in cellular growth and division (Barbet et al, 1996). The mTOR pathway has been found to be highly conserved in a variety of organisms and rapamycin has consistently been effective at inhibiting mTOR (Jacinto and Hall, 2003)
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