Vascular Clinical Research Training Program
John A. Heit, M.D. (Vascular Medicine and Hematology Research)
Epidemiology, Molecular Epidemiology, Mechanisms, Prevention, Diagnosis and Therapy of Thrombosing and Bleeding Disorders
The long-term objective of Dr. Heit's research program is to describe the epidemiology (including genetic epidemiology) and identify mechanisms of venous thromboembolism (VTE, thrombophilia). Using the resources of the Rochester Epidemiology Project, Dr. Heit has identified the 30-year inception cohort of Olmsted County residents with a first lifetime episode of deep vein thrombosis or pulmonary embolism. With this inception cohort, he described trends in the incidence of VTE over this 30-year period, as well as outcomes after VTE, including survival and VTE recurrence, as well as predictors of survival and recurrence. He also identified an Olmsted County resident without VTE matched to each VTE case on age, gender, and medical record number, and performed a nested case-control study. Dr. Heit tested over 100 baseline characteristics as potential risk factors for VTE. In a subset of cases and controls, we collected plasma and DNA samples. He has developed an automated method for rapidly screening genomic DNA for unknown mutations using denaturing high-pressure liquid chromatography (DHPLC). In addition, he has developed assays for rapidly screening known mutations (allele detection) using allele-specific hybridization. With these assays and plasma samples, Dr. Heit is performing candidate-gene, case-control studies to identify single nucleotide polymorphisms ("mutations") which predict a change in either protein expression or function and are associated with VTE (either causative or protective), test for the independence of these mutations as risk factors for deep vein thrombosis or pulmonary embolism, and test for interaction of these mutations with other environmental exposures. With this information, he will be able to better stratify patients into high and low-risk for VTE and either modify risk factors or target prophylaxis to those patients who would benefit most. Moreover, he is testing these mutations and exposures as predictors of VTE recurrence. Finally, Dr. Heit is testing whole blood thrombin generation, basal and stimulated monocyte tissue factor mRNA levels, circulating "free' tissue factor and microparticle-associated tissue factor, circulating activated protein C (APC) activity, platelet ATP secretion and P-selectin expression to ADP and thrombin receptor activation peptide (TRAP), and circulating cytokine levels as potential risk factors for incident VTE and predictors of recurrent VTE. With this information, he will also target both primary and secondary anticoagulant-based prophylaxis to those patients who would benefit most.
A second research program in the Heit laboratory addresses bleeding disorders among women. Specifically, this program addresses potential disorders of platelet function as the etiology of idiopathic menorrhagia among women of reproductive age. In addition to assessing the role of platelet dysfunction, this program also addresses novel therapies for menorrhagia (e.g., antifibrinolytic therapy or DDAVP therapy) as an alternative to hysterectomy or endometrial ablation.
Robert D. McBane, M.D. (Vascular Medicine and Hematology Research)
Individual Propensity for Arterial Thrombosis
One goal of Dr. McBane's laboratory is to understand variables influencing the individual's propensity for arterial platelet-rich thrombus formation. Using a porcine model of carotid crush injury, Dr. McBane has found evidence supporting the existence of a basal predisposition to arterial thrombosis independent of vascular disease. He has determined that blood borne variables contribute significantly to this propensity relative to variables within the vessel wall. Of these blood borne variables, Dr. McBane has shown a direct correlation between platelet deposition and circulating platelet and lymphocyte counts. Dr. McBane is currently studying the contribution of platelet age and specific platelet adhesion and aggregation receptor density to this process in humans with arterial occlusive disease. Major technologies used in his laboratory include flow cytometry and perfusion chamber models. Dr McBane is also active in preclinical antithrombotic drug evaluation using a porcine carotid injury model of platelet rich thrombus generation. Lastly, in conjunction with Dr. Wysokinski, Dr. McBane's laboratory are defining the histomorphology of thrombi formed in patients with atrial fibrillation in an attempt to understand the pathogenesis of thrombosis in patients with this dysrhythmia.
Waldemar E. Wysokinski M.D., Ph.D. (Vascular Medicine and Hematology Research)
Thrombogenesis in Atrial Fibrillation.
The primary focus of Dr. Wysokinski's research is the understanding of thrombogenesis under non-laminar flow conditions as might be seen in atrial fibrillation or aneurysmal disease of the aorta. His laboratory is currently focusing on the role of ADAMS-TS 13 (Von Willebrand factor Cleaving protease) activity and the regulation of platelet deposition as it relates to Von Willebrand Factor metabolism. In conjunction with Dr. McBane, Dr. Wysokinski has recently demonstrated that the architecture of thrombi in atrial fibrillation closely resemble arterial thrombi as opposed to stasis thrombi as previously thought. Major technologies used in Dr. Wysokinski's laboratory includes immunohistochemistry, flow cytometry and perfusion chamber models.
W.G. Owen, Ph.D. (Hematology Research/Biochemistry & Molecular Biology)
Platelet and coagulation factor activation
Dr. Owen's laboratory is interested in the control of biological systems by macromolecular assemblies consisting of proteases, protease precursors and regulatory subunits. These macromolecular assemblies are being studied in the context of platelet activation, prothrombinase, thrombin, plasminogen activation and angiogenesis. The program encompasses regulation of the hemostasis system, the surveillance system for vascular anomalies arising from injury, environmental input, or disease. The primary focus is the protease thrombin, which regulates both the procoagulant and anticoagulant pathways of hemostasis. Pathways under investigation include the Protease-Activated Receptor (PAR) assembly on platelets (thrombin is the protease), thrombin specificity, Ca(II)-mediated folding and membrane assembly of the thrombin zymogen prothrombin, microenvironmental regulation of thrombosis by sodium and calcium ions, the basis for individual propensity to thrombosis (thrombophilia), the impact of infection on thrombosis propensity, the relation of steroid hormones to vascular disease, development of diagnostic markers of pre-symptomatic ischemic vascular disease, extracorporeal thrombosis with model biomaterial systems, and the enzymology of the hemostasis system in vivo. Special methodologies include biophysical measurements of protein structure, including analytical centrifugation for quaternary structure, fluorescence spectroscopy for folding reactions, isolated heart perfusion for endothelial biochemistry, and ultra-dilute platelet culture for platelet biochemistry and metabolism.
David N. , Ph.D. (Hematology Research)
Thrombogenesis and Anti-protease Autoantibodies
There are two main areas of interest in the Fass laboratory. First, in an effort to define the participants in the formation and localization of the platelet plug, the early steps of hemostatic plug formation and thrombogenesis are being modeled in a flow chamber system. When cross sections of artery are exposed to whole blood at physiologic shear rates, the pattern and extent of platelet deposition are analyzed by videomicroscopy. Platelet inhibitors and antibodies to platelet, plasma, and matrix components are used to deplete various components and assess the effect on thrombogenesis.
The second area of focus is the study of immune networks in patients with autoantibodies. Focusing on two particular disorders associated with autoantibody production, we are testing the hypothesis that one modulating factor in the function of autoantibody is the occurrence of concomitant blocking antibody. We are analyzing antibodies from individuals with inhibitors of coagulation factor VIII for evidence of such specificities. In addition, we are attempting to generate monoclonal antibodies that bind to factor VIII but do not inhibit it. Dr. Fass predicts that this would be the hallmark characteristic of a blocking antibody. In conjunction with the laboratory of Dr. Ulrich Specks, Dr. Fass is defining the characteristics of the autoimmune response seen in Wegener's granulomatosis. These patients produce an antibody to autologous proteinase 3, a neutrophil granule elastase-like enzyme. He is isolating the pure protease from mammalian expression systems and producing monoclonal antibodies to characterize epitopes and the alterations of function in proteinase 3-antibody complexes. There is evidence in this disease that there may be pathogenetic and silent (or protective) antibodies, the ratio of which may determine the cyclic flare-ups of inflammatory tissue destruction. A mouse model of the human disease is being developed to evaluate the ability of selected anti-proteinase 3 antibodies to protect against the disease causing variety.
Iftikhar J. Kullo, M.D. (Vascular Medicine and Biology)
Genetic Epidemiology of Peripheral Arterial Disease, Biomarkers of Peripheral Arterial Disease, Functional Arterial Changes in Atherogenesis
Dr. Kullo's research program is focused on novel biomarkers of peripheral arterial disease (PAD) including genetic and proteomic markers, and physiologic markers such as arterial stiffness and endothelial function. Two major NIH funded projects are currently underway. The first project (Biomarkers of peripheral arterial disease) aims at: a) finding regions of the genome that influence the ankle-brachial index (ABI), a non-invasive measure of PAD; b) assessing whether polymorphic variation in SNPs in candidate genes of atherosclerotic vascular disease are related to the ABI, and c) studying the relationship of novel biochemical markers of atherosclerotic vascular disease to the ABI.
The second project (Functional Arterial Changes in Atherogenesis) aims to assess the relationship of measures of arterial function (endothelial function and arterial stiffness and wave reflection) to subclinical measure of coronary atherosclerosis, novel risk factors for atherosclerosis, and to variation in two candidate genes (eNOS and ACE). Dr. Kullo has mentored several post doctoral fellows in the past. Currently he is a mentor to three fellows.
David J. Driscol, M.D. (Pediatric Cardiology)
Arterial Venous Malformations
Dr. Driscoll's research activities has primarily focused on A-V malformations and specifically Klippel-Trenaunay syndrome. Dr. Driscoll published a description of 252 patients with Klippel-Trenaunay syndrome. He now has demographic, clinical and outcome data on more than 400 patients with this syndrome. Dr. Driscoll organizes the national support group for Klippel-Trenaunay syndrome which meets in the Mayo Medical Center, Rochester, MN every other summer. This meeting includes a scientific symposium for patients and family members. In collaboration with Qing Wang, Dr. Driscoll's work has included the search for genetic factors responsible for Klippel-Trenaunay syndrome. This collaboration lead to the discovery of a unique genetic mutation implicated in this disease (Nature. 2004;427:640-645).
Peter Gloviczki, M.D. (Vascular Surgery)
Venous Bypass Patency
The primary goals of Dr. Gloviczki's research laboratory centers around identifying factors effecting long term patency rates of venous vascular bypass graphs. His laboratory explores morphological and functional characteristics of prosthetic materials implanted into the venous and arterial system. The laboratory is actively elucidating the factors affecting patency of grafts implanted into the venous system including the morphological and functional characteristics of prosthetic patch materials. Dr. Gloviczki is currently exploring the relationship between various endothelial related functions and of patency rates of different vascular grafts. As part of this effort, he is pursuing methodologies to optimize adenovirus-mediated gene transfer into blood vessels. Dr. Gloviczki's laboratory is also in the process of defining mechanisms underlying the ischemic and reperfusion injuries to the spinal cord and prevention of spinal cord injury during occlusion of the thoracic aorta.
Haraldur Bjarnason, M.D. (Vascular Interventional Radiology)
Endovascular Therapy for Thrombotic Venous Occlusive Disease
For the past decade, Dr. Bjarnason research interest has focused on assessing endovascular therapies for patients with both acute and chronic venous thrombotic syndromes. Following deep vein thrombosis, as many as 30% of individuals will develop the post-phlebitic syndrome. Ten percent of these individuals will have a devastating clinical course with recurrent venous ulcers, chronic limb edema and disabling venous claudication. Whereas there are currently between 200 and 600,000 incident cases of venous thromboembolism each year in the United States, this represents considerable morbidity to our society. He has prospectively evaluated several catheter-directed thrombolytic therapies including mechanical thrombectomy, venous angioplasty and venous stenting for patients with this disease. The overall technical success rate has been high with patency rates at one year nearing 80%. He has found that patients with malignant disease fare worse and technical success rates are lower in patients with venous occlusions more than four weeks old compared to those with more recent onset of symptoms. Dr. Bjarnason is currently pursuing studies assessing the optimal anticoagulant regimen following venous stenting in patients with chronic venous occlusive diseases.
Leslie T. Cooper, M.D. (Vascular Medicine)
Immune-mediated Cardiovascular Diseases, Immunology and Immunotherapeutics Program faculty
The long-term objective of Dr. Cooper's research program is to define the mechanisms of immune dysregulation in giant cell myocarditis and chronic dilated cardiomyopathy. Dr. Cooper is an NIH funded investigator whose current interests include acute and chronic myocarditis and large vessel vasculitis. Current funded research includes a clinical trial of a monoclonal anti-CD3 T cell antibody for the treatment of giant cell myocarditis, a clinical trial of immunoadsorption for the treatment of chronic dilated cardiomyopathy, and a proteomics project to describe the mechanisms of inflammation in subtypes of myocarditis and arteritis. Dr. Cooper's educational activities include regular teaching responsibilities in the Mayo Medical School and in post-graduate resident medical education. Dr. Cooper has served as a mentor to NIH-funded minority medical students for the past three summers (T35 HL07766, Michael Joyner, PI) and as the primary mentor for a Merck-Banyu Research Fellowship (2000-2002).
Sherine E. Gabriel, M.D., MPH (Clinical Epidemiology)
Epidemiology of Vasculitis
Dr. Gabriel's research falls under three main methodological categories: Clinical epidemiology, population epidemiology, and health services' outcomes research all examining the risks of connective tissue disease among women. Her work on the epidemiology of Giant Cell Arteritis indicated that the long-term trends in the incidence of this disease were cyclic, with peaks in incidence occurring approximately every six to seven years. This important epidemiological observation supports the hypothesis of an infectious etiology underlying this vasculitis. She is currently elucidating rheumatoid arthritis incidence and prevalence cohorts in order to examine the risk of infections in this disease. This information will be used to compared to the observed risk of infection among RA patients receiving the new therapeutic modalities, especially TNF-inhibitors. Dr. Gabriel's commitment to clinical research also extends to clinical research training. She leads a highly qualified team of clinical investigators from Mayo who oversee a K-30 training initiative.
Ulrich Specks, M.D. (Pulmonary Medicine)
Cellular Biology of Vasculitis
Dr. Specks is the principal investigator of laboratory-based research studies designed to characterize the role of the neutrophil serine proteases, proteinase 3 (PR3) and elastase in the pathogenesis of several vasculitides and lung fibrosis. Specific aims of these studies are to identify epitopes on the PR3 molecule which are preferentially recognized by PR3-ANCA (autoantibodies from patients with Wegener's granulomatosis), to characterize the effect of such epitope-specific PR3-ANCA on biological functions of PR3, and to determine whether the functional effects of PR3-ANCA have a bearing on specific clinical disease manifestations. Furthermore, the laboratory investigates structure-function relationships of PR3 and elastase and their significance in the pathogenesis of lung fibrosis. Dr. Specks is also involved in clinical research studies aimed at the identification of novel, more efficacious and safer treatment modalities for ANCA- associated vasculitis. In particular, Dr. Specks is the principal investigator (PI) for Mayo Clinic of the recently completed Wegener's granulomatosis etanercept trial (WGET), an NIH-funded, multi-center, double-masked, placebo-controlled trial (PI, John H. Stone, M.D., M.P.H, Johns Hopkins University) investigating the benefit of anti-TNF-alpha therapy in remission induction and remission maintenance of Wegener's granulomatosis. Dr. Specks is also the PI of an investigator-initiated pilot trial of Rituximab in patients with treatment-refractory ANCA-associated vasculitis, supported in part by a research grant from Genentech and by the Robert N. Brewer Foundation. Dr. Specks is also the co-PI (with Dr. John H. Stone, Johns Hopkins University) for the large multi-center trial of Rituximab for the treatment of ANCA-associated vasculitis (RAVE) funded by the Immune Tolerance Network. This trial compares rituximab to cyclophosphamide for remission induction, remission maintenance and induction of tolerance in ANCA-associated vasculitis. In addition, Dr. Specks is involved in several other clinical studies designed to enhance the understanding of the clinical manifestations, course and prognosis of Wegener's granulomatosis and other ANCA-associated vasculitides. These include the NIH-funded Vasculitis Clinical Research Consortium (VCRC) for which Dr. Specks is the Mayo PI (PI, Peter A. Merkel, M.D., MPH Boston University, Boston, MA).
E.L. Matteson, M.D. (Rheumatology)
Epidemiology and Treatment of Vasculitis
The objective of Dr. Matteson's research program is to define the epidemiology of vasculitis associated with rheumatoid arthritis. Using the resources of the Rochester Epidemiology Project, he described the trends in the incidence of vasculitis and other extraarticular manifestations of rheumatoid arthritis over four decades. Dr. Matteson is currently assessing genetic polymorphisms which are predictive of the development of vasculitis in patients with rheumatoid arthritis as the first step in defining the mechanism of vasculitis genesis in patients with these disorders. Furthermore, he is actively involved in a project to both develop and validate outcome measures of vasculitis, in a joint collaboration with Dr. J.H. Stone, Johns-Hopkins University and Dr. Peter A. Merkel, Boston University. Dr. Matteson is actively involved in clinical trials in vasculitis including a Multi-Center trial of the Safety and Efficacy of Infliximab in Subjects with Giant Cell Arteritis.
Mariza de Andrade, Ph.D. (Biostatistics)
Statistical Genetics and Linkage Analyses
Dr. Mariza de Andrade, Associate Professor of Biostatistics, chairs the Division of Biostatistics and is an established investigator with a productive track record. Dr. de Andrade has a strong record of methodological development and publication in the areas of genetic epidemiology and statistical genetics. Her primary research interest is in the development of new statistical methods for gene localization involving family-based and case-control designs. Currently she is involved in developing methods for diagnostic, longitudinal and multivariate traits for linkage analysis of quantitative phenotypes using variance components approach. Dr. de Andrade has been actively working with multivariate quantitative traits linkage analysis (including ankle-brachial index in collaboration with Dr. Iftikhar J Kullo ) in families using the Rochester Family Heart Study and in siblings using the GENOA study; other research areas include linkage and association analyses in pancreatic and lung cancers, genome wide and candidate gene association analyses in Parkinson's disease and Multiple Sclerosis, and. Dr. de Andrade has extensive statistical consulting experience in both clinical and basic science research, and has been actively working with several research groups at Mayo Clinic such as Hypertension, Pancreas and Lung cancers, and Neurology. She is also director of two statistical core programs, the NCI grants Pancreatic Cancer Genetic Epidemiology Consortium (R01 CA 97075) and the Mayo Clinic SPORE in Pancreatic Cancer (P50 CA 102701), which includes supervising a team consisting of data analysts, master statisticians and programmers. She has participated and presented at International Conferences, has also participated as peer reviewer at several NIH Genome and Small Business Review Sections, and she is currently an official member of the Genomics Computational Biology and Technology Study Section. She is also investigator, co-investigator and consultant in several NIH funded grants, inside and outside Mayo Clinic, providing substantial and creative statistical input.
Daniel Schaid, Ph.D. (Biostatistics)
Statistical Genetics and Association Analyses
The complex genetic basis of common human diseases and traits necessitates the development of new statistical methods to address new questions and new types of data. The primary focus of Dr. Schaid's research is the development and evaluation of statistical methods for the analysis of genetic data. Much of this effort is motivated by ongoing collaborations in projects that focus on either family-based genetic epidemiology studies (e.g., the study of the aggregation of diseases in families, analysis of quantitative traits, and genetic linkage studies), or genetic association studies with common diseases (e.g., case-control studies). General issues addressed by Dr. Schaid's research are study design, data analysis, and computational methods. As a result of this research, new software is developed and distributed to the research community.
Virginia Miller, Ph.D. (Vascular Biology)
Atherogenesis and Sex-steroids
The focus of Dr. Miller's laboratory is understanding how the structure of blood vessels is altered by changes in blood flow, infection and/or sex-steroids. Changes in the physiology of blood vessels cause structural changes characterized by myointimal formation in vein grafts, postmenopausal atherosclerosis, transplant associated atherosclerosis, venous varicose disease and venous ulcers. Dr. Miller's most recent work is focusing on how estrogen replacement therapy reduces progression of atherosclerosis in postmenopausal women through changes in platelet reactivity and in the identification of a new bacterial life-from that may cause pathological calcification of arteries. Information derived from studies of the regulation of local vasoactive and mitogenic factors produced by endothelial cells of the blood vessel wall and blood elements like platelets and leukocytes will identify potential targets for pharmacological interventions to prevent and treat vascular disease. Dr. Miller's research collaborative group represents a multidisciplinary team including basic scientists and physicians from the following disciplines: physiology, pharmacology, surgery, cardiology, dermatology, nephrology, infectious disease, laboratory medicine and geology. This group employs genetic, molecular, cellular and whole animal physiological techniques as well as state-of-the art imaging tools to evaluate cause and effect relationships between manipulation of the physical environment and vascular remodeling.
Amir Lerman, M.D. (Cardiovascular Medicine)
Atherogenesis and Endothelial Dysfunction
Research performed in Dr. Lerman's laboratory is focused on the role of the endothelium in regulation of coronary vascular tone and growth of early coronary atherosclerotic plaques and risk factors. The program is divided into two main themes: (1) Clinical studies in the Cardiac Cathetherization Laboratory focus on patients with early coronary atherosclerosis and endothelial dysfunction. State-of-the-art technologies include intracoronary Doppler, intracoronary pressure assessment and intravascular ultrasound. The Center for Coronary Physiology exists within the Cardiac Catheterization Laboratory for collecting and analyzing data. (2) Animal studies to focus on the role of the endothelium and endothelial-derived factors on the early stages of atherogenesis. (3) In vitro studies include large and micro vessels organ bath, immunohistochemical studies for in-depth investigation of the role of the endothelium in cardiovascular diseases.
Robert D. Simari, M.D. (Cardiovascular Medicine)
Gene Therapy for Cardiovascular Disease
The primary goal of Dr. Simari's laboratory is to investigate and treat cardiovascular disease through modulation of gene expression. Dr. Simari has developed three specific areas of interest in the broad field of cardiovascular disease. Within each aim, he is identifying new targets and developing vectors with therapeutic aims. The first of these aims is to inhibit thrombosis at the sites of vascular injury. Dr. Simari is currently exploring the role of tissue factor pathway inhibitor (TFPI) in this process. Although expressed in diseased vessels, TFPI is expressed in relatively minor amounts compared to its protagonist tissue factor. Dr. Simari has developed genetically modified mice and methods of genetic overexpression to study these diseased states. In addition, Dr. Simari has developed a vascular approach to the treatment of heart failure by overexpressing chimeras of natriuretic peptides using nonviral and viral vectors from the myocardium. Future work will be aimed at optimizing delivery strategies to reach levels that will be therapeutic in the prevention of heart failure. Lastly, Dr. Simari is examining the angiogenic function of early endothelial progenitor cells and late outgrowth endothelial cells in response to vascular injury. Recent experimental observations suggest that bone marrow-derived cells may contribute to both endothelial replacement and neointimal smooth muscle in multiple models of vascular injury. Furthermore, the identification of circulating vascular progenitors in adult blood and the ability to generate enriched populations in vitro have provided new opportunities to directly modify the response to vascular injury. These data have led to the hypothesis that circulating endothelial progenitor cells or their progeny incorporate into injured arteries and attenuate the vascular response to injury.
Stephen J Riederer, Ph.D. (Radiology)
Magnetic Resonance Imaging and Vascular Disease
Dr Riederer's overall research interest is in the technical development of magnetic resonance imaging (MRI). The general goals of research in his laboratory are to attempt to address fundamental limitations of MRI as well to consider new applications of MRI. Recent work has involved the development of a variety of techniques for obtaining MR images in relatively short acquisition times. This includes continuous real-time imaging with sub-second acquisition times per image, imaging over a single period of suspended respiration in order to avoid respiratory artifact, and imaging over multiple periods of respiration. The assumption in the development of many of these projects is that by freezing or avoiding respiratory motion, and in some applications cardiac motion, improvements in image quality can be obtained, particularly in the ability to see structures in the thorax and abdomen. Ongoing projects in these areas include imaging of abdominal organs and vasculature, and of the heart, great vessels, and coronary arteries. In addition to the development of fast MRI pulse sequences, research in his laboratory also focuses on high speed signal processing techniques. This includes instant or "real-time" image reconstruction, interactive control of scanning parameters, and use of low resolution MR images or data to guide the acquisition of data for high quality images. Finally, another aspect of the research in Dr. Riederer's laboratory is focused toward neurological imaging. This includes the development of pulse sequences with increased sensitivity to pathology as well as the development of functional neuro MRI techniques for assessing brain physiology.
John Huston, III, M.D. (Radiology)
Carotid Atherosclerosis and Aneurysms
Research interests include cerebral vascular diseases specifically aneurysms and atherosclerotic disease of the carotid arteries. NIH funded projects include the International Study of Unruptured Intracranial Aneurysms (ISUIA), Familial Intracranial Aneurysm (FIA) Study and Progression of Atherosclerotic Plaque Project. The ISUIA study investigates the natural history of incidentally discovered intracranial aneurysms and the FIA study is looking for the genetic basis of aneurysms. Supporting this focus on cerebral vascular disease is a long term interest in MR angiography.
James Greenleaf, M.D. (Radiology)
Ultrasound Characterization of Arterial Properties
Dr. James Greenleaf's laboratory is active in the area of ultrasound imaging, ultrasound therapy, and ultrasound theory. The laboratory develops new methods of imaging based on theoretical and practical discoveries and collaborates with several research laboratories in clinical departments. Dr. Greenleaf has NIH funding to study arterial properties using Stimulated Acoustical Emission. The long-term goal of this project is to produce methods for measuring and imaging low-frequency material properties of arterial tissues with high resolution and contrast using novel ultrasound stimulated acoustic emission method developed by Dr. Greenleaf and colleagues. The resulting noninvasive measures of arterial stiffness would be amenable to studies in populations. Trainees are assigned projects that range from very basic theoretical development to applied ultrasonic therapy and/or imaging depending on their abilities and interests. Very often trainees are mentored both by Dr. Greenleaf and by a clinical researcher during collaborative research projects. Trainees present their weekly progress at the Monday morning meetings and regularly present their material at national and international meetings in addition to publications.
Richard Ehman, M.D. (Radiology)
Magnetic Resonance Imaging and Vascular Disease
The objective of Dr. Ehman's program is to expand the range of tissue, organ, and system characteristics that can be noninvasively evaluated with magnetic resonance imaging (MRI) techniques. These studies include investigation of new methods for high resolution magnetic resonance imaging of moving structures, techniques of ultrafast MR imaging, and methods for noninvasive mapping of the vascular system. Studies of the basic physics of motion effects in the MR data acquisition process have lead to the development of "Navigator echo" imaging techniques that are highly suited for resolving structures that are in motion. Other studies employ MRI to quantitatively assess vascular flow characteristics such as velocity, volumetric rates, and disordered flow or turbulence. Research is also directed at developing novel MR techniques to measure cellular organization in space and to noninvasively delineate the mechanical properties of the arterial wall. The objective of the latter project is to develop a technique for "palpation by imaging" to detect arterial wall abnormalities at an early stage. The research employs MRI to directly image propagating acoustic waves, allowing images of viscoelastic properties of the arterial wall to be generated.
Dev Mukhopadhyay Ph.D. (Biochemistry/Molecular Biology)
Vascular Biology and Tumor Angiogenesis: Angiogenesis, the formation of new capillaries, is an essential process in many physiological and pathological events
In cancers, new vasculature promotes tumor growth and metastasis. We are examining how tumors develop and, particularly, how they induce the angiogenic response that is essential for their survival. Vascular permeability factor/vascular endothelial growth factor (VPF/VEGF) has been implicated in the new vessel development found in most tumors including renal cell carcinoma and breast cancer. Although the mechanism of these complex processes remain unclear, we are investigating the importance of VPF/VEGF as well as its signaling pathways to elucidate the mechanisms by which VPF/VEGF functions in a variety of tumor models. Moreover, we are also studying the role of other angiogenic related factors such as VEGF C and VEGF D and PIGF in tumor angiogenesis and metastasis. Nanotechnology: The use of nanotechnology in biology has grown over recent years, incorporating the use of reagents such as gold nanoparticles to directly deliver bioconjugates. We are examining the use of these gold nanoparticles and other bioconjugates as messengers to deliver reagents that are capable of manipulating the angiogenic response in vivo.
Thom W. Rooke, M.D. (Vascular Medicine)
Wound Biology and Wound Healing
Dr. Rooke's research interest has primarily focused on the role of microvascular perfusion and tissue oxygenation in the biology of wound healing. He has pioneered the use of devices to measure tissue partial pressure of oxygen transcutaneously. These measures have become standard practice in the evaluation and treatment of patients with critical limb ischemia, vascular and nonvascular wound assessment, and the preoperative prediction of surgical wound healing potential following limb amputation. Dr. Rooke has also pioneered the use of modalities for augmenting microvascular tissue oxygenation, particularly with the use of intermittent pneumatic compression devices, now common in the armamentarium of wound healing modalities.
Mark Pittelkow, M.D. (Dermatology)
Dr. Pittelkow's laboratory has focused on the basic science of wound biology. His laboratory studies the interrelation between epidermal growth, differentiation and integrity and their direct implications in wound healing, inductive angiogenesis and re-epithelialization. His laboratory is studying the effects of various procoagulant, fibrinolytic and inflammatory cytokines and mediators derived from epidermis and skin and their involvement in microvascular homeostasis and pathology.
Neil E Kay, M.D. (Hematology Research)
Cell Biology, Apoptosis, Chronic Lymphocytic Leukemia B-Chronic Lymphocytic Leukemia (CLL) is a common and currently incurable leukemia that is featured by clonal B cells with little proliferative potential but a high level of resistance to apoptosis. This apoptosis resistance is redundant with many different mechanisms that are the ultimate goals of much of our work on this disease. Our main focus is to study the basic biology of the CLL B cell with a focus on uncovering unique and sensitive measures for both prognosis and treatment approaches. Since high levels of blood leukemic B cells are a typical feature of this leukemia it is an ideal model for repetitive in vitro laboratory studies. In order to better evaluate the prognosis and treatment spectrum for these patients we are currently carrying out the following projects: a) utilization of both genomic and proteomic surveys of the leukemic B cells from sporadic CLL patients, CLL patients with familial history and from CLL patients about to enter onto clinical trials. This information will be used to both find unique B cell signatures, genes that are differentially expressed for certain CLL B cell clones and uncover genes or gene patterns related to drug resistance b) Analysis of risk stratification parameters both novel and traditional in untreated and in CLL patients going to clinical trials in relation to clinical course. This type of study is being undertaken in order to better counsel individual patients and determine which of this heterogenous disease may require earlier therapy. c) Determine the autocrine and / or paracrine pathways that the CLL B cell uses in order to escape apoptosis. These studies have already allowed us to discern major pathways that predominate in this leukemic B cell and subsequently allowed design of unique clinical trials. In this investigation many of our questions are conducted after the CLL B cell has interacted with marrow stromal elements in order to discern the influence of the microenvironment on drug resistance and apoptosis in general. Since much of the abnormalities that are found in this B cell malignancy are shared in other tumor types we believe that this work will be related to these other diseases and thus have even farther ranging impact on human malignancy.
Michael Joyner, M.D. (Anesthesia)
Circulatory Physiology and Vascular Tone
The research focus of the laboratory is on the interaction between reflex and local factors which govern whole body circulatory responses to physical and mental stress in humans. We are interested in the cardiovascular responses to thermal stress in humans, the cardiovascular responses to exercise in humans, the cardiovascular responses to orthostatic stress in humans, and the cardiovascular responses to mental stress in humans. At this time we are specifically interested in the role of nitric oxide as a potential mediator of various vasodilatory responses in humans and whether or not this nitric oxide is derived from the vascular endothelium or other sources. We are also interested in the competition between sympathetic vasoconstriction, active vasodilation, and local metabolic factors regulating blood flow to a variety of tissues under a variety of circumstances. Recent new research projects have focused on gender-related differences in circulatory responses to stresses and whether estrogen, endogenous or exogenous, plays a role. In general, we study conscious humans and apply sophisticated cardiovascular and neurophysiologic techniques to them. Many of these subjects are instrumented for intraarterial drug infusions and measurement of blood flow to various tissues. We also measure whole body gas exchange and cardiac output. In addition to our studies in conscious humans, we are also interested in the clinical epidemiology of blood utilization, blood substitutes, and the use of autonomic drugs in anesthesia in medical practice.