The Adar-Mavs Pathway Is A Critical Mediator of The Innate Immune System In Pancreatic Development and Cancer

<p>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 <em>in vitro</em> and <em>in vivo</em> 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.</p>

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Dissertation (PhD)

Year dc:date.available

2022

Authors dc:creator

• Rupani, Dhwani
• <p>https://orcid.org/0000-0003-2325-4057</p>

Contributors dc:contributor

• Florencia McAllister
• Menashe Bar-Eli
• Anirban Maitra

• ADAR
• RNA editing
• pancreatic cancer
• pancreatic development
• MAVS
• Cancer Biology
• Developmental Biology

Repository record dc:identifier

https://digitalcommons.library.tmc.edu/utgsbs_dissertations/1225

OAI identifier oai:identifier

oai:digitalcommons.library.tmc.edu:utgsbs_dissertations-2282