Biomedical Sciences and Engineering MS Thesis Defense by Cansu Karakaya

KOÇ UNIVERSITY

GRADUATE SCHOOL OF SCIENCES & ENGINEERING

BIOMEDICAL SCIENCES & ENGINEERING

MS THESIS DEFENSE BY CANSU KARAKAYA

Title: Gene Expression during Aortic Arch Development and Remodeling in Chick Embryos-A Time Lapsed Network Analysis

Speaker: Cansu Karakaya

Time: January 23, 2018, 10:00

Place: ENG 208

Koç University

Rumeli Feneri Yolu

Sariyer, Istanbul

Thesis Committee Members:

Assoc Prof. Kerem Pekkan (Advisor, Koc University)

Prof. Nesrin Özören (Boğaziçi University)

Assist. Prof. Yap Choon Hwai (National University of Singapore)

Abstract:

Embryonic aortic arches (AA) are bilaterally paired, transitional vessels that are subjected to large-scale vascular morphogenesis and remodeling. Failures in AA patterning based on hemodynamic and growth-related adaptations cause a spectrum of congenital heart disease (CHD) anatomies. It is critical to identify regulatory mechanisms and cross-talk between the genetic elements of these vessels to understand the etiology of CHD and incorporate this information to refine predictive computational models. In our previous work, we reconstructed the three-dimensional (3D) time-lapsed growth data of chick AA in terms of vessel diameter and wall shear stress (WSS) values. The current study aims to screen expression profiles of fundamental biological pathways in the AA at early embryonic Hamburger-Hamilton Stages (HH) of 18, 21 and 24 in the chick embryo, and correlate these data with our previous vascular growth and mechanical loading results. RT-qPCR was performed for angiogenesis, cardiovascular development, and structural and apoptosis-related genes for the left and right lateral arches. Correlation and novel peak expression analysis were conducted in order to compare the behavior and activation period of the associated genes. Available protein networks were integrated with our time-resolved data to investigate the interactions between molecules and highlight major hierarchies to be used in future computational predictions. Based on these analyses, two types of expression patterns, correlated to changes in WSS and diameter, were detected. It was observed that the WSS has a major effect in the regulation of genetic activity, which may contribute to the early left/right patterning of aortic arches. Effect of WSS was seen directly on angiogenesis-related genes other than TGFβ2 as well as extracellular matrix, cytoskeleton and apoptosis-related genes. Our time-resolved network demonstrated that genes correlated with the WSS coordinate the activity of critical growth factors such as VEGF, FGF8 and TGFβ2. Moreover, differences in the gene expression of left and right AA might be an indicator of later asymmetric morphogenesis of the AA. These findings may further our understanding of the complex processes of cardiac morphogenesis and errors that result in CHD.