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Dynamics of Endothelial Metabolomics in Vascular Development and Repair.

紀錄類型:	書目-電子資源 : Monograph/item
書名/作者:	Dynamics of Endothelial Metabolomics in Vascular Development and Repair.
作者:	Beebe, Tyler James.
出版者:	Ann Arbor : : ProQuest Dissertations & Theses, , 2016
面頁冊數:	165 p.
附註:	Source: Dissertation Abstracts International, Volume: 77-05(E), Section: B.
Contained By:	Dissertation Abstracts International77-05B(E).
標題:	Biomedical engineering.
ISBN:	9781339364995
摘要、提要註:	Hemodynamic shear stress is intimately linked with endothelial metabolic effects, regulating key mechanisms in endothelial function, homeostasis, and repair. In-vivo modulation of shear stress signaling pathways in the zebrafish model allows for identification of mechanisms with potential therapeutic implications. The following studies combine in-vivo zebrafish models with in-vitro shear stress studies to characterize the mechanisms whereby shear stress regulates vascular development and repair.

Dynamics of Endothelial Metabolomics in Vascular Development and Repair.
Beebe, Tyler James.

Dynamics of Endothelial Metabolomics in Vascular Development and Repair. - Ann Arbor : ProQuest Dissertations & Theses, 2016 - 165 p.

Source: Dissertation Abstracts International, Volume: 77-05(E), Section: B.

Thesis (Ph.D.)--University of California, Los Angeles, 2016.

This item is not available from ProQuest Dissertations & Theses.

Hemodynamic shear stress is intimately linked with endothelial metabolic effects, regulating key mechanisms in endothelial function, homeostasis, and repair. In-vivo modulation of shear stress signaling pathways in the zebrafish model allows for identification of mechanisms with potential therapeutic implications. The following studies combine in-vivo zebrafish models with in-vitro shear stress studies to characterize the mechanisms whereby shear stress regulates vascular development and repair.

ISBN: 9781339364995Subjects--Topical Terms:

218538
Biomedical engineering.

Dynamics of Endothelial Metabolomics in Vascular Development and Repair.
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245 1 0 $a Dynamics of Endothelial Metabolomics in Vascular Development and Repair.
260 1 $a Ann Arbor : $b ProQuest Dissertations & Theses, $c 2016
300 $a 165 p.
500 $a Source: Dissertation Abstracts International, Volume: 77-05(E), Section: B.
500 $a Includes supplementary digital materials.
500 $a Adviser: Tzung Hsiai.
502 $a Thesis (Ph.D.)--University of California, Los Angeles, 2016.
506 $a This item is not available from ProQuest Dissertations & Theses.
520 $a Hemodynamic shear stress is intimately linked with endothelial metabolic effects, regulating key mechanisms in endothelial function, homeostasis, and repair. In-vivo modulation of shear stress signaling pathways in the zebrafish model allows for identification of mechanisms with potential therapeutic implications. The following studies combine in-vivo zebrafish models with in-vitro shear stress studies to characterize the mechanisms whereby shear stress regulates vascular development and repair.
520 $a We investigated shear stress-modulated genes via microarray, and identified Angiopoietin-2 (Ang-2), a well known regulator of angiogenesis and vascular development, as a potential target for further mechanistic study. Oscillatory shear stress (OSS) induced Ang-2 mRNA expression in a Wnt-signaling dependent manner. Inhibition of Wnt signaling or Ang-2 expression supressed endothelial cell migration and tube formation, which were rescued by human recombinant Ang-2 treatment. These results were recapitulated in the embryonic zebrafish model using heat-shock inducible transgenic Tg(hsp70l:dkk1-GFP) and Tg(kdrl:GFP) embryos injected with Ang-2 morpholino. Inhibition of Wnt signaling with IWR-1 also impaired vascular repair after tail amputation, which was rescued by injection of zAng-2 mRNA. Taken together, this data demonstrated shear stress activated Ang-2 via canonical Wnt signaling in vascular endothelial cells, and recapitulated shear stress-Wnt-Ang-2 signaling vascular repair in the zebrafish model.
520 $a Shear stress-modulated gene- and protein-based mechanisms result in significant changes at the metabolomic level. In the second part of my thesis, we examined the role of emerging mechano-sensitive metabolic pathways in vascular repair. Metabolomic analysis revealed both pulsatile shear stress (PSS) and OSS significantly increased endothelial glycolytic metabolites, but decreased gluconeogenic metabolites. Additionally, both OSS and PSS up-regulated the expression of PKC&egr;. We therefore tested whether shear stress modulates endothelial metabolomics to promote vascular repair via PKC&egr;-mediated glycolytic metabolites. Treatment with pro-glyocolytic metabolites in-vitro rescued tube formation following treatment with siPKC&egr;. To recapitulate vascular repair in transgenic Tg(flk1:GFP) zebrafish embryos, we decreased viscosity and fluid shear stress by micro-injection of GATA-1a morpholino oligonucleotide (MO). In the zebrafish tail amputation model, GATA-1a MO impaired and delayed vascular repair. Co-injection of PKC&egr; mRNA with GATA-1a MO rescued this phenomenon. Injection of epo mRNA to increase viscosity resulted in enhanced tail repair. Overall, our studies revealed that shear responsive VEGFR- PKC&egr;-metabolomic signaling modulates glycolytic metabolites to influence vascular repair.
520 $a Mitochondria are the metabolic center of the cell, and mitochondrial state is intimately linked to endothelial function. To further investigate the effect of shear stress on endothelial metabolic function, we examined the effect of physiological pulsatile shear stress (PSS) on mitochondrial membrane potential (Deltapsim) and the role of Mn-SOD expression on Deltapsim. PSS induced a dynamic increase in Deltapsi m, while silencing Mn-SOD attenuated PSS-mediated Deltapsi m increase. Mn-SOD mimetic MnTMPyP increased Deltapsim to the similar extent as induced by PSS. Our findings suggest that PSS modulates mitochondrial function by increasing mitochondrial Deltapsim, in part, via Mn-SOD up-regulation.
520 $a In addition to using the embryonic zebrafish model to investigate vascular repair, we worked to develop technologies enabling the use of the adult zebrafish as a model for genetic and chemically-induced cardiomyopathies. To address the confounding effects from sedation of fish and removal from the aquatic habitat for micro-electrocardiogram (microECG) measurements, we developed waterproof and wearable flexible electronic sensors to uncover the circadian variation in heart rate (HR) and heart rate variability (HRV). Innovations including an ultra-soft silicone integrated jacket, matching Young's modulus to the fish surface, and embedded micro-glass spheres to reduce the effective density enabled physiological ECG telemetry in the fish's natural habitat without the need for sedation. The novel features of the flexible silicon jacket for microECG telemetry unraveled the biological clock and normalization of QT intervals at following ventricular resection at 26 days post ventricular amputation, providing the first evidence of new physiological phenomena during cardiac injury and repair. Additionally, we revealed Amiodarone-mediated QTc prolongation, HR reduction and HRV increase otherwise masked by sedation. This light weight and waterproof design holds promise to advance the next generation of mobile health and drug discovery.
590 $a School code: 0031.
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710 2 0 $a University of California, Los Angeles. $b Bioengineering. $3 686970
773 0 $t Dissertation Abstracts International $g 77-05B(E).
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791 $a Ph.D.
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793 $a English