Browsing by Author "Ibrahim, Sara Mohommad"

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    miR-21 Exacerbates Cytokine Induced Beta Cell Dysfunction via Inhibition of mRNAs Regulating Beta Cell Identity
    (2020-05) Ibrahim, Sara Mohommad; Sims, Emily K.; Mirmira, Raghu; Benson, Eric; Liu, Yunlong; Mosley, Amber
    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.