MicroRNAs (miRs) are small non-coding RNAs that play crucial roles in regulating mRNA stability and translational repression. There is increasing evidence that miRs can modulate gene expression in the cardiovascular system. Endothelial cells (ECs) lining the vascular lumen are sensitive to mechanical factors such as fluid shear stress. During the past two decades, this research team has worked on the mechanisms of mechanotransduction in ECs and the consequent gene expression. The results from them and others indicate that steady and pulsatile shear stresses (PS) with a net forward direction are anti-atherogenic by inducing genes involved in anti-proliferation and anti-inflammation. In contrast, oscillatory shear stress (OS) without a significant forward direction is pro-atherogenic by activating pro-proiferative and pro-inflammatory genes. Based on new evidence in the literature and our recent findings that miRs play an important role in regulating EC genes, we hypothesize that anti-atherogenic (PS) and pro-atherogenic (OS) flow patterns induce distinct patterns of miRs, and hence the differential gene expressions and functional consequences. We will use in vitro, in vivo, and in silico approaches to develop an integrated system to elucidate the roles of miRs in regulating EC functions in response to different flow patterns. This multi-P.I. research project, by combining experimental data obtained from cultured ECs and mouse models with molecular, genomics and systems approaches, will elucidate the mechanisms of functional regulation by miRs in ECs under flows. In order to test our hypothesis, we propose the following five specific aims: (1) To establish miR expression profiles in cultured ECs in response to PS vs. OS. (2) To determine the target mRNAs of miRs in response to PS vs. OS. (3) To decipher the functional gene expression profiles regulated by miRs under PS vs. OS. (4) To elucidate the functional consequences of miR regulation under PS vs. OS. (5) To verify the role of miRs in functional regulation of vascular ECs exposed to different flow patterns in vivo. In this proposal the role of miR in regulating vascular functions will be studied under different flow patterns with a combination of experimental and computational approaches to perform multi-scale analyses from miRs/mRNAs to cellular functions. This innovative, multidisciplinary project includes (a) comprehensive genome-wide approaches to establish the miR profiles in ECs, (b) CLIP-seq approaches to elucidate the interactions between miRs and target mRNAs, (c) systems biology approaches to map the functional gene expression and biological consequence regulated by miRs, and (d) in vivo approaches in lesion-induction mice to validate the roles of miRs under different flow patterns established in vitro. The results will enhance the mechanistic insights of the roles of mechano- regulation and functional genomics at the systems biology level and may contribute to the development of novel approaches for the diagnosis and treatment of cardiovascular diseases.

Public Health Relevance

MicroRNAs (miRs) are small non-coding RNAs that play crucial roles in the regulation of mRNA stability and translational repression, leading to the modulation of ~30% of the human genome. We will use in vitro, in vivo, and in silico technologies to develop an integrated systems approach to elucidate the roles of miRs in regulating endothelial functions in normal and pathophysiological flow conditions. The result may and may contribute to the development of novel approaches for the diagnosis and treatment of cardiovascular diseases

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Bioengineering, Technology and Surgical Sciences Study Section (BTSS)
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Hasan, Ahmed AK
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University of California San Diego
Biomedical Engineering
Schools of Arts and Sciences
La Jolla
United States
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Miao, Yifei; Ajami, Nassim E; Huang, Tse-Shun et al. (2018) Enhancer-associated long non-coding RNA LEENE regulates endothelial nitric oxide synthase and endothelial function. Nat Commun 9:292
Tsimikas, Sotirios (2018) In search of a physiological function of lipoprotein(a): causality of elevated Lp(a) levels and reduced incidence of type 2 diabetes. J Lipid Res 59:741-744
Tsimikas, Sotirios; Fazio, Sergio; Ferdinand, Keith C et al. (2018) NHLBI Working Group Recommendations to Reduce Lipoprotein(a)-Mediated Risk of Cardiovascular Disease and Aortic Stenosis. J Am Coll Cardiol 71:177-192
Senders, Max L; Que, Xuchu; Cho, Young Seok et al. (2018) PET/MR Imaging of Malondialdehyde-Acetaldehyde Epitopes With a Human Antibody Detects Clinically Relevant Atherothrombosis. J Am Coll Cardiol 71:321-335
Yeh, Yi-Ting; Serrano, Ricardo; François, Joshua et al. (2018) Three-dimensional forces exerted by leukocytes and vascular endothelial cells dynamically facilitate diapedesis. Proc Natl Acad Sci U S A 115:133-138
Diez-Cuñado, Marta; Wei, Ke; Bushway, Paul J et al. (2018) miRNAs that Induce Human Cardiomyocyte Proliferation Converge on the Hippo Pathway. Cell Rep 23:2168-2174
Torzewski, Michael; Ravandi, Amir; Yeang, Calvin et al. (2017) Lipoprotein(a) Associated Molecules are Prominent Components in Plasma and Valve Leaflets in Calcific Aortic Valve Stenosis. JACC Basic Transl Sci 2:229-240
Moriarty, Patrick M; Varvel, Stephen A; Gordts, Philip L S M et al. (2017) Lipoprotein(a) Mass Levels Increase Significantly According to APOE Genotype: An Analysis of 431?239 Patients. Arterioscler Thromb Vasc Biol 37:580-588
Yeang, Calvin; Gordts, Philip L S M; Tsimikas, Sotirios (2017) Novel Lipoprotein(a) Catabolism Pathway via Apolipoprotein(a) Recycling: Adding the Plasminogen Receptor PlgRKT to the List. Circ Res 120:1050-1052
He, Ming; Chen, Zhen; Martin, Marcy et al. (2017) miR-483 Targeting of CTGF Suppresses Endothelial-to-Mesenchymal Transition: Therapeutic Implications in Kawasaki Disease. Circ Res 120:354-365

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