Date of Award

January 2021

Document Type

Thesis

Degree Name

Medical Doctor (MD)

Department

Medicine

First Advisor

Fred Gorelick

Abstract

Pancreatic diseases range from acute pancreatitis to pancreatic ductal adenocarcinoma (PDAC) and can lead to significant morbidity and mortality. Recent literature findings suggest that estradiol and renalase (RNLS) expression may be associated with pancreatic disease severity. Although clinical studies associate estradiol with more severe acute pancreatitis, few studies have explored whether estradiol directly increases severity. We hypothesized that estradiol could increase pancreatic severity and examined this in mouse models. Additionally, though animal studies have shown that tissue levels of the survival factor renalase increases tumor growth in PDAC, few studies have explored whether plasma levels of RNLS might also relate to PDAC severity. We therefore hypothesized that like human PDAC tissues, increased plasma RNLS levels would correlate with increased PDAC severity in clinical settings. We assessed pancreatitis severity in the cerulein-model of pancreatitis in ovariectomized (OVX) mice and mice treated with estradiol. Additionally, we collected clinicopathologic data through retrospective chart review of patients with tissue proven PDAC and assessed correlation between clinical features of disease and plasma RNLS levels. In the OVX mouse model, reduced estradiol levels were associated with less severe pancreatitis that worsened with estradiol treatment. We also found that patients with higher levels of plasma RNLS had worse overall survival and worse features of PDAC disease than patients with lower plasma RNLS levels. Our findings suggest that estradiol and RNLS may play roles in increasing the severity of pancreatic diseases in various contexts. Future studies should explore the pathophysiological mechanism of severe disease and evaluate the potential of use of anti-estrogen or anti-RNLS molecules for mitigation of pancreatic disease severity.

Comments

This thesis is restricted to Yale network users only. This thesis is permanently embargoed from public release.

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