Date of Award
2014
Document Type
Master's Thesis
Degree Name
Master of Science in Biological Sciences (MS)
College, School or Department Name
Department of Biological Sciences
Advisor
Xiaoqing Tang
Abstract
MicroRNAs (miRNAs) are small non-coding RNAs that inhibit gene expression at transcriptional or post-transcriptional level. Let-7 family is among the first identified human miRNAs and regulates multiple cellular processes including glucose metabolism in multiple organs. It has been reported that overexpression of let-7 resulted in insulin resistance and impaired glucose tolerance through repressing insulin signaling pathway in both muscle and liver. However, the role and mechanism underlying let-7 function in pancreatic beta-cells have yet to be elucidated.
Let-7 family contains nine members, which poses a significant challenge in complete deletion of this miRNA family. To study the function of let-7 and to overcome the functional redundancies of various let-7 members in pancreatic beta-cells, the highly expressed let-7a and let-7b were blocked simultaneously using short tandem target mimic (STTM) approach developed in our laboratory. Introducing STTM-let7 into beta-cells markedly increased the expression of Caspase 3, a direct target of let-7, confirming a sufficient functional knockdown of let-7a/b by STTM-let7. STTM-let7 enhanced apoptotic cell death induced by cytokine, indicating that let-7a/b is able to protect from apoptosis through attenuating Caspase 3 expression in pancreatic beta-cells. In contrast to the previous observation that let-7 silencing increases insulin signaling in muscle and liver, inhibition of let-7 with STTM-let7 significantly repressed glucose-stimulated insulin signaling in pancreatic beta-cells, leading to impaired insulin secretion and reduced beta-cell proliferation. Taken together, an appropriate level of let-7 is essential in maintaining beta-cell function and viability. Dysregulation of let-7 may contribute to the pathogenesis of type 2 diabetes.
Recommended Citation
Zhang, Shungang, "ROLE OF MICRORNA LET-7 IN PANCREATIC BETA CELLS", Master's Thesis, Michigan Technological University, 2014.