I am a practicing vascular surgeon with an interest in clinically relevant vascular biology. I graduated from the University of Massachusetts Medical School in 2001. While pursuing my medical degree, I performed research in cardiovascular physiology. Upon completion of my degree, I trained in general surgery at the Beth Israel Deaconess Medical Center in Boston, Massachusetts. I was able to interrupt for two years for a post-doctoral fellowship. It was during this time that I began some of the work on which my lab now focuses. After completion of general surgery residency I matriculated to the University of California, San Francisco for a vascular surgery fellowship. During this fellowship I was able to hone my research questions and begin the framework for future grant applications. I came to the University of Maryland in 2010. I am presently funded by grants through the Veterans Administration and the Vascular Cures Foundation. I have close collaborations with several members of the Center for Vascular and Inflammatory Diseases faculty. Being both a practicing surgeon and a scientist allows me to ask clinically relevant research questions and use technically difficult animal models. The University of Maryland fosters an environment that nurtures the “bench-to-bedside-(to-bench)” concept and supports translational research.
My research interests are focused on the treatment of peripheral arterial disease (PAD). To this end, one of our long-term goals is to identify differential mechanisms of regulation of vascular smooth muscle cell and endothelial cell proliferation. Proliferation of these two different cell types is a key event in response to arterial injury, such as is observed after angioplasty, stenting, or bypass. Intimal hyperplasia, the vascular response to iatrogenic arterial injury, is characterized by increased vascular smooth muscle cell proliferation. Present strategies to prevent the formation of intimal hyperplasia include the use on antiproliferative agents. However, these agents also inhibit endothelial cell proliferation mandating that the patient receive dual antiplatelet therapy indefinately. An ideal therapeutic agent would exert a differential effect on proliferation of these two cell types. Previously, we have identified a protein kinase C substrate, the myristolated alanine-rich C kinase substrate (MARCKS), that when knocked down in vitro inhibits vascular smooth muscle cell proliferation with minimal effects on endothelial cell proliferation. Our initial experience with MARCKS knockdown suggests that this protein might be important for differential regulation of vascular smooth muscle cell and endothelial cell proliferation. Our present efforts seek to identify the mechanism by which MARCKS knockdown differentially affects vascular smooth muscle cell and endothelial cell proliferation and to determine if the differential effect persists in vivo.
Regardless of the target for therapy, the agent needs to reach the target tissue. Proliferation is a key cellular function in all cell types and consequently administering a potent antiproliferative agent systemically would doubtlessly cause many undesirable side effects. We have been using siRNA to achieve knockdown of MARCKS in vivo in rodent models of intimal hyperplasia. We elected to pursue siRNA-mediated knockdown for two reasons. First, it has a relatively well-defined half-life and duration of effect; the siRNA is divided between each of the daughter cells after each cell division. Second, virtually any sequenced gene or combination of genes can be silenced using this approach. We have developed protocols for in vivo transfection with siRNA in a mouse model. We are anticipating working a method of delivering siRNA in a large animal model using both catheter-based and open surgical techniques.
Finally, there are patients whom do not have a patent distal artery to which to bypass and consequently, these patients are declared non-reconstructable. Several previous trials have evaluated treatment of these limbs with stem cells to induce vasculogenesis. However, the logistics involved with these trials made this approach impractical. We are exploring alternate methods of attracting the stem cell populations that are important in both angiogenesis and arteriogenesis to an ischemic limb. We are presently using a mouse model of hind limb ischemia to test our hypothesis.
Our laboratory is located in the Center for Vascular and Inflammatory Diseases. This location facilitates collaboration with other researchers interested in different aspects of Vascular Biology. We also have access to the many core facilities ad both the CVID and the School of Medicine. This setting is an optimal environment to perform this type of translational research.