Indiana University-Purdue University Indianapolis (IUPUI) / A hallmark of diabetes is the loss of physical or functional Beta (β) cell mass.
Maladaptive intrinsic β cell responses to islet inflammatory stress may exacerbate
diabetes development, suggesting that β cells themselves may not be innocent bystanders
in diabetes development. MicroRNAs (miRNAs), small RNAs that repress mRNA
translation, serve as important regulators of β cell development and function. β cell
microRNA 21 (miR-21) is increased in models of diabetes and I have identified Hypoxia
Inducible Factor 1 Subunit Alpha (Hif1a) as a regulator of β cell miR-21. However, β cell
effects of miR-21, remain poorly defined. To define the effects of miR-21, an in silico
analysis of predictive targets of miR-21 identified multiple targets associated with
maintenance of β cell identity, including the SMAD Family Member 2 (Smad2) mRNAs
in the Transforming Growth Factor Beta 2 (Tgfb2) pathway. Based on this, I
hypothesized that β cell miR-21 induces dysfunction via loss of β cell identity. To test
this, I developed a tetracycline-on system of miR-21 induction in clonal β cells and
human islets, as well as novel transgenic zebrafish and mouse models of inducible β cell
specific miR-21 overexpression. β cell miR-21 induction increased aldehyde
dehydrogenase (aldh1a3), but reduced expression of transcription factors associated with
β cell identity, and glucose stimulated insulin secretion (GSIS), consistent with β cell
dedifferentiation and dysfunction. Predicted targets Tgfb2 and Smad2 were reduced by
miR-21 overexpression and confirmed to directly bind miR-21 using streptavidin-biotin
pulldown. In vivo models of β cell miR-21 induction exhibited hyperglycemia, increased glucagon expression, and decreased insulin expression. These findings implicate miR-21-
mediated reduction of mRNAs regulating β cell identity as a contributor to β cell
dedifferentiation and dysfunction during islet inflammatory stress. / 2022-05-19
| Identifer | oai:union.ndltd.org:IUPUI/oai:scholarworks.iupui.edu:1805/22834 |
| Date | 05 1900 |
| Creators | Ibrahim, Sara Mohommad |
| Contributors | Sims, Emily K., Mirmira, Raghu, Benson, Eric, Liu, Yunlong, Mosley, Amber |
| Source Sets | Indiana University-Purdue University Indianapolis |
| Language | en_US |
| Detected Language | English |
| Type | Dissertation |
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