The research focus on the effects of mechanical force on Cardiovascular diseases (CVD).
Specifically, shear stress generated from blood flow plays an important role in the physiological or pathological function of endothelial cells, which composes the inner layer of blood vessels. Disturbed blood flow resulting in low and oscillatory shear stress leads to atherosclerosis and affects the progression of angiogenesis (new vessel formation). The ultimate goal of the research is to understand critical mechanisms which cause CVD and subsequently identify essential genes that will serve as major targets for drug discovery. Currently, the research is utilizing Zebrafish as an animal model to screen vascular deficits associated with specific genes and will apply the entire approach to rodent study as well as human research in the near future.
Hemodynamic forces provide environmental cues guiding vascular remodeling. The abnormality of this process results in diseases but the detail mechanism is unclear. Specifically, local mechanical forces generated by blood flow have been correlated to the behavior of the exposed endothelium. Given the fact that scientists, including us, have investigated the profiles of gene expression in response to different flow patterns, the knowledge, however, is still lacking for the role of each specific gene in the process. Since vascular remodeling plays a key part in the progression of several diseases including cancer and cardiovascular diseases, a critical and essential step is to have a better understanding of the mechanism in the molecular level, which leads to develop an efficient treatment for human diseases. Importantly, determining the role of flow-regulated genes provides insights into the potential therapeutic strategy against related diseases. Therefore, this proposal will address an important question regarding the function of stab2 in flow-dependent endothelial remodeling, in terms of the regulation of long non-coding RNA. Since the progress of vascular disease is based on vessel remodeling concomitant with gene expression changes, a better knowledge of flow responsive genes (stab2) and regulatory molecular (lncRNA:9587) may help in the therapeutic manipulation of blood vessels to treat cardiovascular diseases.
Funding: Al Jalila Foundation, seed grant 2015-2016
PI: Dr. Chih-Wen Ni
Determining Vascular Functions of Novel Flow-Sensitive Genes Using Reverse Genetic Screening in Zebrafish
In vertebrate animals, blood flow provides oxygen to cells, removes metabolic waste, and supports immune and endocrine systems. Hemodynamic forces generated by blood flow provide environmental cues guiding vascular development and play unique roles to maintain physiological function in endothelial cells (ECs). It is known that disturbed flow induces endothelial dysfunction and contributes to atherosclerosis; however, the detail mechanisms have not been fully elucidated. To better understand the effects of flow on vascular pathophysiology, it is important to identify and study the function of flow-responsive regulatory pathways. Zebrafish has been used as a model system to identify flow-responsive genes in ECs during embryonic development. Based on my preliminary studies, I have identified a set of genes, which showed significant alteration of expression level in the presence and absence of blood flow. We will then select at least 10 genes and perform reverse genetic screening to examine vascular phenotype on generated mutants. Hence, this proposal will address an important question regarding the function of flow-sensitive genes in vascular development and remodeling, which induced by blood flow. Therefore, a better knowledge of flow responsive genes and associated regulatory pathways may help in the therapeutic manipulation of blood vessels to treat cardiovascular diseases.