Honors College Thesis

 

The Effects of Rapamycin on the Unfolded Protein Response in Relation to Healthy Aging Public Deposited

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https://ir.library.oregonstate.edu/concern/honors_college_theses/7d278v83j

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  • The loss of proteostasis is the mechanism for maintaining properly folded proteins and degrading misfolded ones. One protective mechanism against loss of proteostasis is the Unfolded Protein Response (UPR), a chaperone mediated folding system in the Endoplasmic Reticulum (ER). The UPR communicates with the Nrf2 pathway, a transcription factor, and rapamycin, a drug that increases health span in several mammalian models. We hypothesized that the protective effects of rapamycin can be mediated by activation of Nrf2 to regulate UPR pathways. Nrf2 WT and KO mouse embryonic fibroblast cells were pretreated with rapamycin under positive stressors, and key UPR chaperone protein levels and activation were measured by standard Western blot and polymerase chain reaction protocol. In general, rapamycin pretreatment protected against Thapsigargin most efficiently in WT cells. Nrf2 KO cells showed overall lower levels of chaperone protein activation, indicating Nrf2 deficiency increasing cell susceptibility to ER stress. The data also indicated that Nrf2 has important buffering capacity in certain UPR pathways, as variation of protein expression changed in only WT cells. Therefore, our hypothesis seems to be supported by the data and we further hypothesize that rapamycin’s effects would decrease protein aggregation and increase health span through regulating the UPR response. Key Words: health span, rapamycin, unfolded protein response, Nrf2
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