 Vascular Surgery: Conrad Jobst Vascular Surgery Research LaboratoryThe Conrad Jobst Vascular Surgery Research Laboratories occupy approximately 2,800 square feet of space in Medical Science Research Building II. Four designated units represent the core of these laboratories: a cell biology unit, a biochemistry unit, a large animal operating room, and a small animal study unit. Projects within these laboratories have generated external funding from industrial sources as well as the National Institutes of Health and local and national heart associations. The Cell Biology Unit is dedicated to the study of cellular structure and function of the arterial and venous wall. Incubators and two-person laminar-flow hoods with appropriate support equipment allow for the study of endothelium and vascular smooth muscle in the tissue culture environment. Programs defining vascular smooth muscle, and endothelial cell function, in particular, have been established and include interdisciplinary collaborations with molecular geneticists, physiologists and biochemists. Studies in this unit are related to gene transfer experiments, the study of endothelial cell and smooth muscle growth kinetics, as well as the regulation of extracellular matrix proteins in the vascular wall. The interface between the thrombus and the vein wall is another focus of investigation in models of venous thrombosis. The Biochemistry Unit is dedicated to the study of normal and diseased vessels at the molecular level, as well as the effects of disease processes on organ and limb function. A major portion of activity in this laboratory is directed at investigating the blood surface interface and coagulation system, and studying the vascular responses to injury using molecular biology techniques. Collaborative efforts involve interdisciplinary programs with cell biologists, physiologists and biochemists. A second major focus is the study of the molecular mechanisms controlling extracellular matrix production and degradation in vascular wall cells in vitro and in vivo. The Operating Room is a state-of-the-art animal operating facility, that allow acute and sterile surgical procedures. A carefully designed and monitored environment is necessary for the implantation of vascular substitutes as well as other devices placed within the circulatory system. This unit also facilitates studies regarding regulatory physiology. The effects of vascular diseases and surgical procedures on cardiac and pulmonary function, as well as specific physiologic activities of the brain, kidney, intestine, muscle and skin are studied in this facility. Additionally, operative stations for small animal surgery are available. The focus of research involves studies into venous thromboembolism, pulmonary embolism, and aortic aneurysms. Members of the Jobst laboratory have active collaboration with faculty and staff from Internal Medicine, Pathology, Psychology, Radiology and the Unit for Laboratory Animal Medicine (ULAM). Techniques
Equipment
Investigators
Location/Laboratory Contacts
P-selectin is Central to Venous Thrombosis Pathogenesis
Investigators: Thomas Wakefield, MD (PI), Daniel Myers, Jr DVM, Peter Henke MD The project evaluates the role of P-selctin in the pathogenesis of venous thrombosis. Anti-inflammatory and Pro-inflammatory Cytokine Balance in Venous Thrombosis
Investigators: Thomas Wakefield MD, J. Brian Fowlkes PhD., (Ultrasound), David. Williams M.D., (Radiology) This project investigates the cellular and molecular mechanisms of inflammation in response to venous thrombosis in rat and mouse models of IVC thrombosis, specifically evaluating IL-10's role in the inflammatory and thrombotic process. Prospective Investigation of Pulmonary Embolism Diagnosis II
Investigators: Paul Stein MD (PI); Jack Weg MD (PI, Pulmonary Medicine, Subcontract); Thomas W. Wakefield MD (Ultrasound Chair) The project compares spiral CT scanning to pulmonary angiography with the use of lower extremity venous duplex imaging for the diagnosis of pulmonary embolism. Aging Venous Thrombi with Ultrasound Elasticity Imaging
Investigators: Jon Rubin MD (PI, Radiology); Stanislav Emelianov PhD (Biomechanical Engineering), Matthew O'Donnell PhD (Biomedical Engineering), Daniel Myers, Jr DVM, Thomas W Wakefield MD This project will use a new technique of elasticity quantification to age venous thrombi. Prevention of Recurrent Venous Thromboembolism (Prevent)
Investigators: Melvin Rubinfire MD (PI, Cardiology), Thomas Wakefield MD This project evaluates the efficiency of prolonged treatment with low-dose warfarin after idiopathic DVT. Thrombus Resolution is CXC Chemokine Dependent
Investigators: Peter Henke MD (PI), Thomas Wakefield MD The project evaluates factors responsible for thrombus resolution after DVT. Inhibition of DVT Induced Inflammation and Thrombosis by rPSGL-Ig
Investigators: Thomas Wakefield, MD (PI), Daniel Myers, Jr DVM, Shirley Wrobleski, BS, LVT, Frank Londy, RT (Radiology), Peter Henke, MD, Lazar J. Greenfield, MD This project evaluates the use of a PSGL-1 receptor antagonist to limit inflammation and thrombosis during and after venous thrombosis produced by temporary venous balloon occlusion. It also assesses the ability of the same PSGL-1 receptor antagonist to augment spontaneous venous thrombolysis. Validation of the Hope Model for Outpatient Treatment of DVT
Investigators: Mary Proctor MS (PI), Thomas Wakefield MD This project will validate a model for the outpatient treatment of deep venous thrombosis using LMWH. Inhibition of Deep Vein Thrombosis (DVT)-Induced Inflammation and Thrombosis by Melagatron
Investigators: Thomas Wakefield MD (PI), Daniel Myers, Jr DVM, Shirley Wrobleski BS, LVT This project will assess the effects of Melagatron in an IVC ligation model. Use of Ultrasound Contrast for Thrombus Identification
Investigators: Thomas Wakefield MD (PI), J. Brian Fowlkes PhD, Daniel Myers DVM This project will use ultrasound contrast agents to identify DVT. Supervised Calf Muscle Exercise in Patients with Chronic Venous Insufficiency and Wearing Compression Stockings
Investigators: Paul Zajkowski, BS, Thomas Wakefield MD, Mary Proctor MS, Thomas Draper (Preventive Cardiology) This project will determine the effect of a supervised exercise program on venous insufficiency. Enhancing Intrinsic Regeneration to Tissue Engineer a Peripheral Nerve Graft
Investigators: William Kuzon (PI, Plastic Surgery), Thomas Wakefield MD The project will examine the role of inflammation and its inhibition in peripheral nerve graft biology. The Use of Large Public Data Bases for the Determination of Outcomes of HealthcareInvestigators: Lloyd A. Jacobs, M.D. This program constitutes an exploration of the utility of large public databases to answer questions related to surgical outcomes, cost of intervention, as well as rates of deaths and complications. For example, a recent exploration of the Department of Veterans Affairs patient treatment file related to the resection of abdominal aortic aneurysm was undertaken. Complication and mortality rates as well as cost factors are being analyzed. Similarly, this and other large databases are being queried for information relative to frequency of carotid endarterectomy, as it may have been impacted by the results of the "Asymptomatic Carotid Artery Study." Additional spin-off projects include analysis of the cost of complications and case load analysis for surgeons in different age groups. The analyses for the above-mentioned projects are at various stages completed for abdominal aortic aneurysmectomy and well underway for carotid endarterectomy. Changing Institutional Dynamics and their Relationship to Leadership BehaviorsInvestigators: Lloyd A. Jacobs, M.D., Richard Cofey, Ph.D. Academic Health Centers (AHC's) are being subjected to rapid change, most of it driven by intense external sociological forces. Faculty members practicing at such centers are experiencing significant diminution in autonomy, in life time earning potential, and in choice of career venue. This may have a negative impact o nresearch productivity as well as the commitment to teaching which constitute thecore VALUE system of most AHC's. The hypothesis that these negative effects can be ameliorated by leadership training is being investigated. Two specific projects are presently under way:
Modulation of Nitric Oxide Alters MMP Expression by Vascular Smooth Muscle and Endothelial Cells.
Investigators: Gilbert R. Upchurch, Jr., MD, John W. Ford, BA, James C. Stanley, MD The purpose of this study is to better characterize the role of nitric oxide, known to be important in vessel wall remodeling, on matrix metalloproteinase (MMP) expression both in vitro and in vivo. MMPs are a superfamily of enzymes that play a role in a number of disease processes including aneurysm formation, rheumatoid and osteoarthritis, and angiogenesis. Data has demonstrated that decreases in nitric oxide lead to a selective increase in MMP-9 production. Further characterization of this in vitro finding is ongoing in the elastase perfused aortic aneurysm model. Differences in MMP Expression in the Thoracic and Abdominal Aorta in Male and Female RatsInvestigators: Gilbert R. Upchurch, Jr., MD, John W. Ford, BA, Karen Roelofs, DVM, and James C. Stanley, MDFunding: National Institutes of Health and Lifeline Foundation Our laboratory is focused on MMP-9, an enzyme felt to be critical in the development of AAAs. We are exploring transplantation of the thoracic and abdominal aorta in rats. Also, using an elastase perfusion model, we have examined differences between males and females rodents and their ability to generate aneurysms. Ongoing experiments using the elastase perfusion model to examine the role of various glycoproteins in knockout mice will be performed. Surgical Outcomes Research Team (SORT)
Investigators: Gilbert R. Upchurch, Jr., MD, Justin B. Dimick, MD, John A. Cowan, Jr., MD, Peter K. Henke, MD, James C. Stanley, MD We have developed an interest in outcomes research which has extended to cover the breadth of all of General Surgery. Through these studies, we have shown the effects of hospital volume on abdominal aortic aneurysm repair, aortofemoral bypass, thoracoabdominal aneurysm repair, as well as carotid endarterectomy. In addition, general surgical procedures, including hepatic and pancreatic resection, have also been examined. The data available to us spans 13 years from the National Inpatient Sample (NIS). The NIS allows us to examine mortality as a primary endpoint following various surgical procedures across the United. Doxycycline in Patients with Abdominal Aortic Aneurysms (UMHS)
Investigators: Gilbert R. Upchurch, Jr., MD, James C. Stanley, MD We hope to participate in a NIH-sponsored multicenter trial which seeks to examine the effects of doxycycline, a known nonspecific MMP inhibitor, on aneurysm growth in patients with small nonoperable abdominal aortic aneurysms (AAAs). This trial is closely linked with an internal trial in our General Clinical Research Center, which has been examining the effects of doxycycline in patients with large nonoperative AAAs. The Role of COPD in Patients with Abdominal Aortic Aneurysms: The Influence on COPD on Length of Stay and Mortality.
Investigators: Gilbert R. Upchurch, Jr., MD, Mary C. Proctor, MS, James C. Stanley, MD Over the last ten years at the University of Michigan, data has been accrued on all patients undergoing abdominal aortic aneurysm repair. A special focus has been placed on patients with chronic obstructive pulmonary disease. A database is presently in place that examines the influences of medications such as steroids and inhalers on morbidity, length of stay, and mortality. In addition, a large Veteran's Administration database is being incorporated in order to increase the significance of this study. Chemokine Mediated Deep Vein Thrombosis Resolution
Investigators: Peter K. Henke, MD, Andrea J. Varga, BS, Thomas W. Wakefield, MD The purpose of this study is to define the role of CC and CXC chemokines on the resolution of a deep vein thrombosis in a mouse and rat model. Specifically, investigation will focus on the role of these chemokines in mediating leukocyte influx, angiogenesis and fibrinolysis using chemokine receptor knockouts and neutrophil depletion strategies. The long-term goal is to develop therapeutic avenues to speed thrombosis resolution to decrease the risk of pulmonary embolism and chronic venous insufficiency. Deep Venous Thrombosis Resolution is CXC Chemokine-dependent
Investigators: Peter K. Henke, MD, Andrea Varga, BS, Pasu Sukheepod, MD, Thomas W. Wakefield, MD The purpose of this study is to define the role of CXC chemokines in DVT resolution, along with their effect on PMN lytic activity in vitro. Pulmonary Artery and Fibrotic Lung Disease Associated with Pulmonary Embolism
Investigators: Peter K. Henke, MD, Catherine Luke, BS, Thomas W. Wakefield, MD, Lazar J. Greenfield, MD Pulmonary embolism is a devastating disease that has an early mortality of at least 30%, and subsequent long-term morbidity primarily due to pulmonary hypertension. The basic pathophysiology of a PE has not been well defined in an animal model, nor the long-term pathophysiology of pulmonary hypertension that often results. The goal of this study is to explore the role of proinflammatory mediators in the pathophysiology of PE in a rat model and correlate this with associated pulmonary artery leukocyte influx and fibrosis. Rheumatologic Disease's Role in Peripheral Vascular Occlusive Disease
Investigators: Peter K. Henke, MD, Thomas W. Wakefield, MD, Leslie J. Crofford, MD, Alvin Schmaier, MD The role of rheumatologic disease in peripheral vascular occlusive disease is not well defined outside of the known arteritides, such as giant cell arteritis. Furthermore, the use of COX-II inhibitors in these patients has markedly increased and may unmask a tendency toward thrombosis, as has been observed anecdotally. The goal of this study is twofold; first, to define the interrelation of rheumatologic disorders with PVOD and secondly, determine if COX-II inhibition is associated with an increased risk of arterial thrombosis and what conditions may predispose them to such. Deep Vein Thrombosis and Malignancy: Risk of Pulmonary Embolism and Chemotherapy
Investigators: Peter K. Henke, MD, Mary C. Proctor, MS, Lazar J. Greenfield, MD Deep vein thrombosis is often the first harbinger of a malignancy and this occurs in up to 20% of patients with a known malignancy, with appreciable morbidity. The risk of pulmonary embolism is also greater in those patients with a malignancy. The time course of this embolic risk in those patients undergoing cytotoxic chemotherapy may be greater, in part secondary to leukopenia and presumed poor thrombus adherence. The goal of this study will be to define malignancies associated with an increase risk of DVT/PE and its relation to certain chemotherapeutic regimens, and then to apply this prospectively with an eye toward prophylactic treatment in those patients at highest risk. |