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Date of Award
2017
Document Type
Campus Access Dissertation
Degree Name
Doctor of Philosophy in Biological Sciences (PhD)
Administrative Home Department
Department of Biological Sciences
Advisor 1
Xiaoqing Tang
Committee Member 1
Guiliang Tang
Committee Member 2
Zhiying Shan
Committee Member 3
Jeremy Goldman
Abstract
In pancreatic beta cells, insulin biosynthesis and secretion is tightly regulated by a network of transcriptional activators and repressors that maintain the fate of beta cells and activate genes in response to the change of plasma glucose. The discovery of small non-coding microRNAs (miRNAs) has added a novel regulatory layer on modulating levels of key components involved in beta cell proliferation, survival, insulin biosynthesis and secretion.
In this thesis, we focused on dissecting the functions of miR-30d, a highly expressed and glucose-stimulated miRNA in pancreatic beta-cells by combining cellular and molecular techniques, high-throughput deep sequencing, mouse and cell line genetic approaches. We have shed light on the novel roles of miR-30d in regulating β-cell mass on the middle-aged mice under high-fat diet treatment. We further demonstrated it induced beta-cell apoptosis and inhibit beta-cell proliferation by targeting variety of gene expression including BCL2 interacting protein 3 (Bnip3) and Cyclin E2 (Ccne2). Furthermore, silencing of miR-30d by advanced CRISPR-CAS9 gene editing system promotes the insulin secretion, which is through potentiated expression of MAFA, an insulin transcription factor. High-Seq analysis and further target searching revealed 13 candidate targets of miR-30d in MIN6 cells involved in various functions. These studies uncovered novel functional roles of the miR-30d pathway in mediating β-cell function and fate. Further dissection shall uncover the mechanisms by which the β-cells utilized to maximize their efficiency during disease states such as T2D.
Recommended Citation
Mao, Yiping, "FUNCTIONAL DISSECTION OF MICRORNA-30D IN MAMMALIAN PANCREATIC BETA-CELLS", Campus Access Dissertation, Michigan Technological University, 2017.