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Understanding the Role of Hypusine Biosynthesis in Exocrine-Endocrine Crosstalk

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Understanding the Role of Hypusine Biosynthesis in Exocrine-Endocrine Crosstalk

thesis
posted on 2022-09-08, 14:05 authored by Dorian DaleDorian Dale

  

Traditionally, the exocrine and endocrine cellular compartments of the pancreas have been considered distinct functional systems. However, recent studies suggest a more intricate relationship between the exocrine and endocrine, which may impact pancreatic growth and health. Additionally, translational control mechanisms have been linked to organ development. Our lab has shown that the mRNA translation factor eukaryotic initiation factor 5A (eIF5A), when in its post-translationally modified “hypusinated” form, plays a role in pancreas development. The hypusination of eIF5A requires the rate-limiting enzyme deoxyhypusine synthase (Dhps) to post-translationally modify a critical lysine residue which in turn produces the active form of eIF5A that functions in mRNA translation. When we generated animals with a deletion of Dhps in the pancreatic progenitor cells, there was no alteration in islet mass but significant exocrine insufficiency at embryonic (E) day 18.5 concomitant with downregulation of proteins required for exocrine pancreas development and function. Resultantly these animals died by 6 weeks-of-age. These observations prompted the question, is the phenotype caused by the absence of hypusinated eIF5A or the increase of unhypusinated eIF5A? To address this, we generated a mouse model wherein Eif5a is deleted in the pancreas (eIF5A∆PANC) and these mutant animals also display exocrine insufficiency. Interestingly, beta cell mass is increased at E18.5, and the mutant animals maintain euglycemia and survive up to 2 years. Ongoing analyses are interrogating the differences between these animal models with the goal to determine if mRNA translation facilitates cellular communication between the exocrine and endocrine pancreas.

Funding

Juvenile Diabetes Research Foundation International (JDRF). Grant Number: 5-CDA-2016-194-A-N

HHS | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). Grant Number: 1R01DK121987-01A1

History

Degree Type

  • Master of Science

Department

  • Biological Sciences

Campus location

  • Indianapolis

Advisor/Supervisor/Committee Chair

Teresa Mastracci

Additional Committee Member 2

Nicolas Berbari

Additional Committee Member 3

Jason Spaeth

Additional Committee Member 4

Lata Balakrishnan