| Chapter 1 of this thesis provides general background of E ndoplasmic Reticulum (ER) stress and the U nfolded Protein Response (UPR). It also describes the tools employed in the literature to study these processes and discusses the need for the development of new strategies to probe the relevant cellular pathways. Finally, it provides a brief summary of the work I have done toward the advancement of these strategies. Chapter 2 contains a detailed literature review of necessary concepts, including the signaling pathways that constitute the UPR. It discusses the various small molecule strategies that have been developed to target individual components of these pathways, and also to target the health of the ER lumen as a whole. This chapter gives special attention to the details of the cell biology of the inositol---requiring enzyme 1alpha (Irel alpha) pathway that have been revealed by existing small molecule ligands that target this protein. Finally, it discusses the therapeutic opportunities that small molecule modulators of this pathway present, and the ongoing efforts to validate Irel alpha as a therapeutic target in various diseases. Chapter 3 details my work in extending the 'Hydrophobic Tagging' technology for protein degradation pioneered by our lab, to the endoplasmic reticulum. It discusses the development of this technology as a strategy for inducing a unique short-lived and non-apoptotic UPR. It subsequently describes the results of an mRNA-sequencing experiment conducted using this system, and the revelation of induction of estrogen signaling as a late-stage consequence of the UPR. It then explores our work investigating the possible role of estrogen signaling as a component of the feedback mechanism within the UPR, and the emergence from our work of the possibility of anti-estrogen therapy in the treatment of Multiple Myeloma. Chapter 4 describes our work toward targeting the Irel alpha pathway with small molecules. The novel ligands that emerge from our study in this regard form the basis for future research, which will aim to increase their potency and investigate their possible utility in indications where Irel is thought to be a validated therapeutic target. Finally, Chapter 5 concludes this dissertation by summarizing the contributions that studies described in the two preceding chapters have made to the current state of understanding of ER stress and the UPR, and offering a perspective on emergent directions from our work that would serve to expand research in this area in exciting new directions. |
