Investigating the role of the basic helix-loop-helix transcription factor MIST1 in pancreatic diseases

<p>Acinar cells of the exocrine pancreas are dedicated to synthesize, package and secrete immense quantities of pro-digestive enzymes to maintain proper metabolic homeostasis for the organism. Dysregulation of enzyme secretion in acinar cells can give rise to exocrine diseases including acute pancreatitis (AP), a disease that targets acinar cells, leading to acinar-ductal metaplasia (ADM), inflammation and fibrosis—events that can transition into the earliest stages of pancreatic ductal adenocarcinoma (PDAC). The focus of this thesis is to interrogate transcriptional regulatory networks that are susceptible to AP and the role that these networks play in acinar cell and exocrine pancreas responses. The overall goal is to determine the importance of the acinar-specific maturation transcription factor MIST1 to AP damage and organ recovery and its role in AP induced PDAC upon oncogenic transformation. Analysis of wild-type and <em>Mist1</em> conditional null mice revealed that <em>Mist1 </em>gene transcription and protein accumulation are dramatically reduced as acinar cells undergo ADM alterations during AP episodes.</p> <p>To test if loss of MIST1 function is primarily responsible for the damaged status of the organ, mice harboring a Cre-inducible <em>Mist1</em>transgene (<em>iMist1</em>) were utilized to determine if sustained MIST1 activity could alleviate AP damage responses. Surprisingly, constitutive <em>iMist1</em> expression during AP produced a dramatic increase in organ damage followed by acinar cell death. This result suggests that the transient silencing of <em>Mist1</em> expression is critical for acinar cells to survive an AP episode, providing cells an opportunity to suppress their secretory function and regenerate damaged cells. In order to further define the role of MIST1 in pancreatic neoplasia lesion formation (a precursor of PDAC), <em>Mist1</em> conditional null mice were generated that contained a mutated oncogenic <em>KrasG12D</em> allele. Direct comparison between embryonic <em>Mist1</em> null mice with conditional <em>Mist1</em> null mice in the context of KRASG12D activity demonstrated that embryonic <em>Mist1</em> null mice are more susceptible to PanIN formation. The importance of MIST1 to these events suggests that modulating key pancreas transcription networks could ease clinical symptoms in patients diagnosed with pancreatitis and pancreatic cancer.</p>

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Biological Science

Year

2016

Author dc:creator

• Karki, Anju

Contributors dc:contributor

• Stephen F. Konieczny
• Ignacio Camarillo
• Daniel Suter
• Weiguo Andy Tao

• Biological sciences
• Health and environmental sciences
• Acinar cells
• MIST1
• Pancreas
• Pathology
• Physiology

Repository record dc:identifier

https://docs.lib.purdue.edu/open_access_dissertations/665

OAI identifier oai:identifier

oai:docs.lib.purdue.edu:open_access_dissertations-1794