Team:BrownTwo/Limiter/utility

The utility of threshold limitation

While cells are usually well-equipped to modulate their own transcriptional behavior, an investigation into pathological gene expression indicates that many situations arise wherein the expected regulatory response fails. Our device is designed to augment endogenous gene regulatory pathways.

• Medical
• Apoptosis (& other) research

-extrinsic pathway in mammals relies on cell-surface communication -death receptors such as Fas, DR5, or TNF receptor-1 bind to their respective ligands and recruit adaptor FADDand caspase-8 => activation of caspase-8 => activation of caspase-3 and caspase-7 Note that IAP (Inibitor of Apoptosis) proteins inhibit the caspases, so they are potential targets for cancer therapy and also appear to be perfect targets for our limiter : ) -this is especially true for human XIAP, which is a potent inhibitor of apoptosis and binds to at least three different caspases -XIAP is inhibited by Smac/DIABLO and Omi/HtrA2, which are released from the mitochondria - AKA: API3; ILP1; MIHA; XLP2; BIRC4 - Fas pathway, inhibited by Smac, which is activated by Bax and Bak (from science’s signaling page)

• Vucic -The IAPs as Therapeutic Targets in Cancer-

check out references 32-35 and 38-40 for more info on how IAPs relate to malignancies check our references 41-43 for more info about how XIAP confounds proapoptotic signals -could conceivably use the up-limiter to increase XIAP expression -alternatively, could up-regulate the factors that cause Smac/DIABLO and Omi/HtrA2 release from the mito Another possible target for down-regulation is Bcl-xL, which prevents the release of cytochrome c into the cytoplasm -activated by STAT3,5 Interestingly, XIAP is turned off by the expression of Bax and Bak (which inhibit Smac) and it inhibits capsase 3 while Bcl-xL is inhibited by caspase 3 and in turn inhibits Bax and Bak (Science signaling) -thus, inhibition of XIAP will result in inhibition of Bcl-xL via caspase 3, both of which will result in promoting apoptosis. Could also target Bax or Bak, since high levels of both will also result in decrease in levels of XIAP and Bcl-xL

-might even want to target both, seeing as they operate at different levels of the apoptosis pathway (Bcl-xL before cytochrome c release and XIAP afterwards)

• directed evolution (includes epigenetics?)