Author ORCID Identifier
Date of Graduation
Doctor of Philosophy (PhD)
Adenosine deaminase acting on RNA (ADAR) is an RNA-binding protein that deaminates adenosine (A) to inosine (I). A-to-I editing is an important post-transcriptional mechanism to prevent recognition of endogenous RNA by MDA5, a cytosolic RNA sensor. Activation of MDA5 by viral RNA can stimulate the innate immune system. Thus, ADAR-mediated RNA editing is crucial to distinguish “self” from “non-self”. ADAR has an important role in gene regulation as A-to-I editing alters RNA processing affecting both RNA and protein abundance. Given its importance in regulating innate immunity and transcript abundance, aberrations in Adar expression are implicated in developmental deformities and carcinogenesis. The work presented in this thesis explores the yet undefined role of Adar in pancreatic development and tumor biology. Through genetic mouse models, we conclusively show that the primary function of Adar in the pancreas is to prevent aberrant activation of the Mavs-mediated innate immune pathway, thereby maintaining pancreatic homeostasis. Pancreatic cancer has a desmoplastic stroma and most immune checkpoint blockade therapies fail to restrict it. Almost 18% of pancreatic cancer patient tumors have an upregulation of ADAR. We evaluated clinical data sets and performed in vitro and in vivo studies to understand the function of Adar in pancreatic cancer. In all, the work presented here highlights the crucial role of Adar in pancreatic development and cancer.
ADAR, RNA editing, pancreatic cancer, pancreatic development, MAVS
Available for download on Friday, November 10, 2023