Cardiovascular diseases such as heart attack and stroke are major causes of morbidity and mortality. According to the CDC, heart disease is the leading cause of death in the United States with approximately 600,000 deaths per year, accounting for one in every four deaths in the US. Improvements in the diagnosis, treatment and prevention of these diseases will benefit countless people, and the resulting improvements in patient health, well-being and productivity will have a major impact on society. Dr. Shu Chien of the University of California, San Diego's Institute of Engineering in Medicine is studying how vessel geometry and pressure affect flow patterns, and how that in turn affects gene and protein expressions in cells lining the blood vessels. This highly interdisciplinary work brings together engineering, biology and medicine to address the major health issue of cardiovascular disease and solve important clinical problems. His research spans from fundamental studies aimed at understanding the mechanisms that govern circulatory regulation to the clinical translation of novel discoveries.The results uncovered by this research have numerous implications for general cardiovascular health, both in the development of preventative measures as well as guidance for surgeons who are tasked with reconstructing or reconnecting vessels in the body. The strides Dr. Chien has made in this field were recognized by President Obama when in 2011 Dr. Chien was awarded the National Medal of Science, the only recipient out of seven nationwide who researches in an engineering discipline. Cardiovascular disease is a widespread problem that results in the death of more people than any other condition, and Dr. Chien is attacking this issue from unique perspectives.

Dr. Chien is investigating the mechanisms by which mechanical forces, such as flow and pressure, and the physical geometric structure of vessels, modulate the functions and structure of the circulatory system. He is taking this a step further, by looking at how that modulation alters the expression of certain genes and proteins in the cells surrounding blood vessels. Essentially, how does blood flow differently through altering vessel conditions and what are the changes that stem from differing blood flow patterns? Similar to water flowing in a river, blood will flow straight and generally uninterrupted through straight pathways of blood vessels. At forks or branches of the vessel, seen commonly throughout the body, the pattern of flow will create eddies and deviate from streamlines. Continuing this analogy, sand deposited at the bottom of a riverbed as result of the currents of water above it is reflective of the way plaque buildup in blood vessels is influenced by the flow of blood. Studying this flow will provide valuable insights into risk factors for cardiovascular disease. Dr. Chien is further working to understand how the conditions of a blood vessel's microenvironment will influence the gene and protein expressions by surrounding cells. Protein expression is generally controlled by the molecular and genetic factors within the cell, and which proteins are expressed differs in areas of different flow patterns. Proteins dictate the behavior and function of the cells, including growth, differentiation, and secretion, and differences in protein expression can be either positive or negative. Advances in mechanobiology and genetics have enabled Dr. Chien to explore this phenomena even deeper by looking at the epigenetic factors and micro-RNA strands that regulate gene and protein expressions. This research is a three-pronged approach with increasing detail: to understand the functions and structure of blood vessels, we must look at the proteins involved, and to understand the protein, we must look at the DNA and RNA involved. A unique and major emphasis of Dr. Chien's research is the interdisciplinary approach he uses, combining engineering, biology, and medicine to identify the molecular and cellular bases blood vessels utilize to maintain their normal function in healthy individuals, and to respond abnormally in individuals with disease. He is using precise medical techniques to locally manipulate the structure or condition of a blood vessel and study the changes that result from that disturbed flow. 

Current research projects are looking at the circulatory system at a number of varied levels of detail, from the effects of blood flow patterns on genes and proteins to stem cells and genetic material:

1. Dr. Chien is investigating the different mechanisms by which different kinds of flow patterns in blood vessels modulate, or influence, the genetic expression and protein synthesis in cells lining the blood vessels. Researching these changes will reveal how the molecules affected are modified by different flow patterns. For example, in areas of poor flow, typically seen at the branch points of vessels, Dr. Chien is working to suppress certain genes through therapeutic manipulation. In areas of positive or beneficial flow, genes and molecules are typically up-regulated, and Dr. Chien is searching for ways to enhance this. If both positive and negative mechanisms are identified, they can be used as specific targets for correcting a number of cardiovascular diseases.

2. Dr. Chien is researching the roles of epigenetics, changes in protein transcription that are not only the results of changes in gene transcription, but rather are also influenced by other factors acting on those genes, for example the microRNAs, which are short RNA strands that regulate longer, protein-coding RNA, to modulate cell function. When looking at changes in the structure and function of a blood cell, one must look not only at the proteins involved, and advances in molecular biology and genetics have allowed scientists to go a step further and study the genetic material responsible for protein transcription. Dr. Chien is interested in seeing what changes manifest in genetic material following, for instance, a change in pressure or flow. If, for example, blood flows from a narrow vessel to a region with a wider outflow, the flow will be disturbed, and Dr. Chien is looking at the effects of these changes on epigenetic factors, and thus protein expression. Identifying the mechanisms that influence both positive and negative effects of flow dynamics will allow for the development of therapeutic approaches. Therapeutic agents, i.e. drug molecules, can modify activity by enhancing or blocking microRNA abilities, if the proper genetic material can be identified.

3. Dr. Chien is looking at how the factors that comprise the microenvironment of a stem cell (flow dynamics, the substrate they sit on, their chemical environment) can determine the behavior of stem cells located in blood vessels, including the growth and differentiation of stem cells. He is testing this by using microarray systems, a "lab-on-a-chip" that allows for screening large amounts of data simultaneously. Dr. Chien places stem cells on an array of proteins (or synthetic polymers) with different compositions and observes the effects of varying protein combinations. This gives insight into which protein combinations may be optimal for guiding the differentiation of a stem cell into a specific cell type. Using a microarray system allows for the testing of hundreds of different protein matrixes in a high-throughput method that is far more efficient than traditional testing methods. The data from this project is being used to develop methods for most effectively guiding stem cell behavior, thus facilitating the further development of more complicated methods of influencing differentiation.