Circulatory system

Timothy Secomb, PhD, studies the microcirculation, a network of extremely small blood vessels that supply oxygen and nutrients to all parts of our tissues. The focus of work in his research group is the use of mathematical and computational approaches to study blood flow and mass transport in the microcirculation. Working in collaboration with experimentalists, the aim is to understand quantitatively the processes involved. Dr. Secomb examines the relationship between red blood cell mechanics and flow resistance in microvessels. Theoretical predictions agree well with observations in glass tubes, but resistance is higher living tissue. The major cause is the presence of a relatively thick macromolecular lining (endothelial surface layer) on the walls of microvessels. He also simulates oxygen exchange between networks of microvessels and surrounding tissues in skeletal muscle and tumors. In skeletal muscle, oxygen can be exchanged diffusively between arterioles and capillaries, and Dr. Secomb’s lab is studying the determinants of maximal oxygen consumption. In tumors, the relationship between network structure and occurrence of local hypoxic (radiation-resistant) regions is a source of curiosity. They are analyzing the delivery of chemotherapeutic drugs in tumor tissues, and developing improved models to describe the responses of tumor cells to chemotherapy and radiation. Models for the structural responses of microvessels to functional demands are being developed. Maintenance of a stable, functionally adequate distribution of vessel diameters can be achieved if each vessel responds to changes in wall shear stress, intravascular pressure and local metabolic conditions, and if mechanisms exist for information transfer upstream and downstream along flow pathways. Models for the active regulation of blood flow by changes in vascular tone are also being developed, taking into account vascular responses to wall shear stress, pressure and local metabolic state, and including effects of conducted responses along vessel walls. Another project in the group is the development of computer simulations for the dynamics of the left ventricle that can be run in real time and provide a tool for analysis of data derived from ultrasound echocardiography images.

Research in my laboratory over the last 30 years has focused on chronic heart failure (CHF), its pathophysiology and the development of new treatments for CHF. We have developed clinically relevant animal models of heart failure that allow us to explore the translational potential of new treatments. Our work initially examined the role of afterload reduction and neurohormal blockade. More recently we have been working with cell-based therapy for CHF using bioengineered scaffolds to prevent left ventricular (LV) remodeling and restore function in the damaged heart. Our most effective scaffold is a biodegradable vicryl mesh with embedded viable neonatal fibroblasts that secrete angiogenic growth factors. This patch increases myocardial blood flow, improves LV systolic function, and reverses LV remodeling if implanted at the time of an acute myocardial infarction. In CHF, this patch still improves myocardial blood flow but does not improve LV function or reverse LV remodeling. Thus, we have an effective delivery system for cell based therapy for CHF that increases myocardial blood flow and provides structural support for new cell growth. We are now focusing on seeding this patch with human inducible pluripotent stem cells in the cardiac lineage, the seeded cardiomyocytes align, communicate, contract in a spontaneous and rhythmic fashion. When implanted in rats with CHF, they improve LV function. We are exploring this patch seeded with human inducible cardiac pluripotent stem cells to treat patients with CHF. Keywords: induced pluripotent stem cells

Thomas Davis, PhD, and his lab continue its long-term CNS biodistribution research program, funded by NIH since 1981, by studying the mechanisms involved in delivering drugs across the blood-brain barrier to the C.N.S. during pathological disease states. Recently, Dr. Davis and his lab discovered specifica drug transporters which can be targeted to enhance delivery. They are also interested in studying the effect of hypoxia/aglycemia/inflammatory pain on endothelial cell permeability and structure at the blood-brain barrier. Dr. Davis has recently shown that short-term hypoxia/aglycemia leads to significant alterations in permeability which can be reversed by specific calcium channel antagonists. This work has significant consequences to the study of stroke. Additionally, he has discovered that peripheral pain has significant effects on BBB tight junction protein cytoarchitecture leading to variations in the delivery of analgesics to the CNS.