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Access Type
WSU Access
Date of Award
January 2023
Degree Type
Thesis
Degree Name
M.S.
Department
Molecular Biology and Genetics
First Advisor
Li Li
Abstract
Fibrillin (FBN1), a glycoprotein, is essential for the formation of elastic fibers in the ECM. FBN1 mutations cause Marfan syndrome. The FBN1Q2467X nonsense mutation was used to create the Fbn1Q2469X/Q2469X mouse model, which develops an aneurysm in the root-ascending-arch region of the thoracic aorta (TA), not in the abdominal aorta (AA). miRNAs play important roles in regulating various signaling pathways and mechanisms connected to altered gene expression. Although, the role of miRNAs in the endothelium remains poorly understood. Using microRNA-seq analyses, we found that miRNA-146b-5p is highly expressed in both thoracic and abdominal aorta of Fbn1Q2469X/Q2469X mice, but not in their WT control mice, suggesting that FBN1 deficiency could induce the expression of miRNA-146b-5p. To identify the factor inducing the miRNA-146b-5p expression, we induced RAoECs with different factors. We found that the miRNA-146b-5p expression increases upon Ang II induction which might be due to the Ang II-EGR1 axis. EGR1 is induced by Ang II and is a potential transcription factor of the miRNA-146b-5p. To screen for the possible targets of miRNA-146b-5p we used the TargetScan and miRDB databases to find: TNF alpha-associate factor 6 (TRAF6) and interleukin-1 receptor-associated kinase 1 (IRAK1) appear to have high scores. Since TRAF6 and IRAK1 are known to play important roles in inflammation through NF-kB activation, the upregulation of miRNA-146b-5p may likely inhibit the expression of TRAF6 and IRAK1 to prevent vascular inflammation during aneurysm formation. In this study, we present evidence validating the expression of TRAF6 and IRAK1 as the targets of FBN1 deficiency-induced miRNA-146b-5p through Ang II-EGR1 axis to protect aorta integrity both in vivo and in vitro along with the signaling mechanism. The miRNA-146b-5p down-regulates NF- kB and thus reduces the increased expression of VCAM1, ICAM1, and CCL2 suggesting its anti- inflammatory role. We also confirm the location of the miRNA-146b-5p in the endothelial cells of the aorta and not as an extra-cellular miRNA.
Recommended Citation
Hemani, Darshi V., "The Potential Protective Role Of Fbn1 Deficiency-Induced Mir146b-5p In Aneurysm Progression In Marfan’s Syndrome." (2023). Wayne State University Theses. 906.
https://digitalcommons.wayne.edu/oa_theses/906