Scientific Preceptors
Fiemu Nwariaku, MD, Associate Professor of Surgery. The Nwariaku laboratory is interested in inflammatory endothelial dysfunction; specifically this laboratory examines the role of intracellular oxidants as mediators of cytokine signaling. Their work indicates that oxidants generated by endothelial NADPH oxidase leads to phosphorylation of junctional proteins and subsequent loss of endothelial barrier function. Their laboratory has expertise in molecular biology techniques including cloning, mutagenesis, construction of viral vectors and immunoblotting. Other techniques in the laboratory include the use of cDNA mini-arrays, confocal microscopy and transmonolayer electrical resistance. He is funded by the NIGMS and the Robert Wood Johnson foundation.
Deborah L. Carlson, Ph.D. Assistant Professor, Department of Pediatrics. Research in the Carlson, I am currently interested in examining the consequences of caspase activation in the heart following injury, independent of apoptosis. Our group is independently examining the roles that caspases -3, and -8 play in mediating cardiac dysfunction, inflammation, and in regulation of transcription factors such as NF-kB, using both transgenic and pharmacologic models. In addition, we are also beginning to asses the role that the inflammatory capase, caspase -1 may play in both mediating the inflammatory and cardiac pathways. Our current results are very encouraging that caspase-1 plays a significant role in mediating the observed cardiac dysfunction, and in regulating expression of other caspases
Frederick Grinnell, PhD Professor of Cell Biology. Research in the Grinnell laboratory examines regulation of cell migration and proliferation by the interaction of growth factors and extracellular matrix. Migration of fibroblasts in three dimensional collagen matrix cultures results in matrix remodeling and contraction, a process that is adaptive and progressive. Molecular signaling and mechanisms that regulate contraction vary according to local matrix organization, and cells switch between proliferative and quiescent states depending upon isometric tension. Tissues and organs are three dimensional structures, and extracellular matrix plays a key role in their organization in vivo. Grinnell and colleagues study this organizational function using three dimensional cultures because they introduce complex patterns of dynamic, cell-extracellular matrix interactions not observable in routine cell culture. Above all, this means on one hand that cells will be completely surrounded by extracellular matrix; and on the other, that cells will be able to remodel the matrix thereby changing matrix properties and, in reciprocal fashion, cell features will then change as well.
Donald Hilgemann, PhD Professor of Physiology. The Hilgemann laboratory studies ion channels and transporters that regulate a wide range of cell functions, from cardiac contraction to vision to secretion. The transporters include a cardiac Na /Ca2 exchange system, the Na /K pump, and sodium-coupled neurotransmitter transporters. The ion channels include potassium channels, which control the rates of electrical activity in tissues from brain to heart to pancreas, and they include ion channels which are opened by cyclic nucleotides whose activity initiates the vision and smell processes. To improve biophysical and regulatory studies of these mechanisms, this lab improved the so-called 'patch clamp' electrophysiological methods to allow them to excise 'giant' membrane patches from many cell types. These methods allow the study of conformational changes of transport proteins with one microsecond resolution, and it is a long-term goal to reconstitute important membrane-associated processes in the patches such as phototransduction, calcium release, and membrane insertion and retrieval. Recently, they discovered that phosphatidylinositides are important regulators of a wide range of ion transporters and channels. They are now studying how enzymes involved in phosphatidylinositide synthesis/degradation are regulated by cell signaling mechanisms, and how ultimately they regulate cell function through modulation of ion transport activities.
Joseph Hill, MD, PhD, Associate Professor of Internal Medicine and Chief of Cardiology. Dr. Hill's research examines molecular mechanisms of structural and electrophysiological remodeling in cardiac hypertrophy and failure. Using molecular, physiological, and electrophysiological approaches, they study mechanisms of structural, functional, and electrical remodeling in heart disease. These studies are based on genetic and surgical models of heart disease in animals, as well as patients with hypertrophic heart disease and cardiomyopathy. Specific questions being studied at present include: mechanisms governing the pathological growth response of the myocardium; autophagy as a novel mechanism of remodeling that contributes to the transition from stable hypertrophy to heart failure; mechanisms of Ca2 metabolism in hypertrophied and failing ventricular myocytes with particular emphasis on transcriptional and post-translational regulation of the L-type Ca2 channel; phosphoinositide-dependent signaling pathways (and downstream targets) in cardiac hypertrophy and failure; and regulation of circadian gene expression by environmental stimuli.
Ahamed Idris, MD, Professor of Surgery, Director, Emergency Medicine Research and The Dallas Center for Resuscitation Research. Dr. Idris leads the Dallas Center for Resuscitation Research, one of 8 US and 2 Canadian centers funded by the NIH, Dept. of Defense, and the Canadian Health Service. This is the first time that resuscitation science has received major funding from national agencies. The purpose of these centers is to study novel interventions that may improve outcome from cardiac arrest and severe traumatic injury. The primary focus of the research centers is to study interventions that can be used by emergency personnel for immediate resuscitation before the patient arrives at a hospital. The Dallas Center alone annually cares for more than 2,000 cardiac arrest patients and 3,600 severe traumatic injuries. All 10 centers collectively have over 10,000 cardiac arrests, and 26,000 traumatic injuries per year. This group conducts controlled trials each year, including controlled ventilation for all intubated patients, hypertonic saline and antioxidants for trauma, recombinant factor VII for severe hemorrhage, and a number of different drugs, hypothermia, and the impedance threshold device for cardiac arrest.
Jane E. Johnson, Ph.D., Associate Professor of Cell Biology, Genetics and Development, and Neuroscience. The development and survival of neurons depends upon an intricate network of interactions between cells. The differentiation of each of the hundreds of cell types in the nervous system results from the expression of a specific set of genes in response to multiple extracellular and intracellular signals. Transcription factors of the basic helix-loop-helix (bHLH) family are involved in the development of neuronal lineages in both invertebrates and vertebrates. Expression of members of one subclass within the bHLH family is restricted to an early stage of neural development during which the decision to proliferate or differentiate is being made. The essential function of this subclass of bHLH factors has been demonstrated in the loss of specific neuronal lineages in mice mutant for these genes. Identifying the upstream regulators of these early expressed genes that include, Mash1, Math1, ngn1, and ngn2, will provide insights into the molecular mechanisms underlying the decision of a proliferating precursor cell to differentiate to a specific type of neuron. Using transgenic mice to assay for regulatory sequences within these genes, Dr. Johnson has begun to uncover the enhancer sequences involved in controlling their expression within the developing vertebrate nervous system. These studies will provide valuable tools to define/manipulate distinct neuronal progenitor populations in multiple regions of the central nervous system.
Steven G. Kernie, MD, Assistant Professor of Pediatrics. The Kernie lab utilizes two genetic systems to study adult neural stem cells. The first came from the observation that adult Bax deficient mice have increased numbers of neural stem cells in the subventricular zone of the lateral ventricles. They have extensively characterized this observation using a neurosphere culture assay and have shown that Bax deficient adult, but not embryonic, neural stem cells are resistant to caspase mediated cell death. This gives them a model of enhanced adult neural stem cells that can be studied both in vitro and in vivo. The second genetic system takes advantage of a new generation reverse tetracycline transactivator known as rtTA-M2. They have generated transgenic mice that express rtTA-M2 and eGFP under the control of the neural precursor specific form of the nestin promoter, and have crossed this mouse with a Tet-OP-Cre expressing transgenic in a stop-LacZ-Rosa26 background demonstrating both sensitivity and specificity in their system. This system now enables them to inducibly trace these cells as well as selectively activate or delete genes that may be important in adult neural stem cell function.
Steven McKnight, PhD, Professor and Chairman, Department of Biochemistry, holder of the Distinguished Chair in Basic Biomedical Research and the Sam G. Winstead and F. Andrew Bell Distinguished Chair in Biochemistry. Genes are switched on and off in eukaryotic cells via regulatory proteins commonly termed transcription factors. The research focus of the McKnight laboratory centers on a subset of transcription factors that are gene specific. In the simplest of terms, a gene may be subject to regulation by a given transcription factor if it contains high affinity binding sites for that factor in a functionally relevant region - promoter, enhancer or silencer. This simplistic dogma is complicated by a variety of complexities that have emerged from studies of eukaryotic gene regulation over the past decade. For example, individual transcription factors tend to exist as members of multiprotein families whose DNA binding activities can be indistinguishable when analyzed as isolated biochemical entities. It is therefore problematic to assess which member of a related family is responsible for a given regulatory event. It has also been recognized that gene specific transcription factors can obligatorily rely on heteromeric partners. A competent DNA binding version, that is, may rely on the formation of a protein complex consisting of two or more entirely distinct polypeptides. In certain cases, gene specific transcription factors retain the ability to bind DNA avidly, yet are unable to functionally regulate transcription at the level of activation or repression without the help of co-activator or co-repressor proteins. Biologic activities of transcription factors are universally regulated in cells by covalent post-translational modification, including phosphorylation and proteolysis, or by non-covalent interaction with small molecule metabolites or ligands.
Michael G. Roth, Ph.D., Professor and Vice Chairman of Biochemistry. The basic unit of life is the single cell and understanding how living organisms function ultimately requires learning how the parts of a cell work together. The components of cells are made in a few locations and then transported to other places where they function and then to yet other locations for disposal. This requires a complex traffic of molecules within the cell, even in a simple cell such as a bacterium. Animal cells are far more complicated than bacteria and are compartmentalized into a number of distinct organelles; each separated from the others by a limiting membrane. The traffic of the lipids and proteins that make up these membranes is exceedingly complex and involves the exchange of small membrane vesicles between organelles. The focus of the Roth laboratory is to understand how these vesicles are formed and how they select the right cargo. They use recombinant DNA technology to make mutant proteins that they introduce into cells to see how they are recognized and transported within the cell. They rely upon a variety of biochemical techniques as well as light and electron microscopy to locate proteins within cells. They use genetics and biochemistry to identify cellular proteins required for the intracellular traffic of membrane proteins and lipids. Because intracellular membrane traffic is very fast, occurring on a time scale of seconds to minutes, they have started a new initiative to look for fast-acting small molecules that can diffuse into cells and inhibit or stimulate membrane traffic. Although the work is basic cell biology, defects in the processes cause human diseases such as cystic fibrosis, Alzheimer's Disease and lysosomal storage diseases.
Philip Shaul, MD, Professor of Pediatrics, and holder of the Lowe Foundation Professorship in Pediatric Critical Care Research. The signaling molecule nitric oxide (NO), produced by the enzyme NO synthase (NOS), plays a major role in vascular and airway homeostasis. Alterations in NOS function are critically involved in the pathogenesis of atherosclerosis and hypertension, and also many lung diseases. Studies in Shaul's laboratory have indicated that the endothelial isoform of NOS (eNOS) is expressed in a cell-specific manner in vascular endothelium and airway epithelium. We have demonstrated that eNOS is transcriptionally regulated by oxygen and estrogen, it is targeted to specialized plasma membrane domains called caveolae or lipid rafts, and its activity is acutely modulated by oxygen, estrogen and high density lipoprotein (HDL). The acute effects of estrogen on eNOS are mediated by a subpopulation of membrane-associated estrogen receptors acting in a novel, nongenomic manner. Regulation by HDL involves scavenger receptor BI, which we have discovered is localized in endothelial cell caveolae. HDL is the most robust agonist for eNOS that has been found to date, potentially explaining the dramatic antiatherogenic properties of the lipoprotein. Further, we have discovered that eNOS localization and function in caveolae are markedly attenuated by oxidized LDL through changes in membrane lipid composition. Cellular and molecular mechanisms underlying regulation of eNOS expression/function are currently under investigation in isolated caveolae membrane preparations, in native endothelial/epithelial cells, and in reconstitution paradigms using wild-type or mutant forms of the enzyme and interacting molecules.
James T. Stull, Ph.D., Chairman of Physiology and holder of the Fouad A Bashour Chair in Physiology, The research in his laboratory addresses two general aspects of actin cytoskeleton regulation: acute and chronic adaptive. First, in acute studies they have concentrated on relating mechanical events manifested during the course of contraction and relaxation to the generation of biochemical intermediates that regulate contractility. Measurements of stress-strain relationships, shortening velocities, and stiffness are used to provide a primary description of physiological function whose molecular basis is explained with the assistance of structural and biochemical studies. Kinetic studies are used to relate rates and sites of phosphorylation of contractile proteins to mechanical activation. The importance of different components of the regulatory pathway (kinases, phosphatases, contractile proteins, etc.) is tested by antisense knockdowns, protein transduction domains, and by permeabilized muscle fibers.
Helen L. Yin, Ph.D., Professor of Physiology The Yin lab has several major research interests: 1) PIP2 regulation cellular functions -- PIP2 is an important signaling and scaffolding lipid and this lab examines the role of PIP2 on regulation of the actin cytoskeleton, receptor mediated endocytosis, and intracellular calcium signaling. 2) Phosphoinositide regulation of Golgi functions -- the Golgi is the central sorting station for membrane trafficking. Phosphoinositides such as PIP2 and PI4P may be modulators of multiple Golgi functions. Yin identified a phosphatidylinositol 4 kinase (which synthesizes PI4P) as a Golgi resident protein, and it is the major source of the cell's PI4P. 3) The effect of burn trauma on phosphoinositide homeostasis and the rationale design of therapeutic targets to decrease the morbidity and mortality associated with burn and burn/sepsis.
Clinical Preceptors
It is important to note that in addition to the assignment of a scientific mentor, each trainee in our program has a clinical preceptor assigned. The role of this clinical preceptor is to aid trainees in relating their basic science efforts to the clinical arena and to provide academic and career counseling. The recent addition of a clinical epidemiology program has been a significant benefit to our training program. Epidemiological and biostatistical resources available through this program are utilized by our trainees; injury surveillance and epidemiology efforts are directed at blunt and penetrating trauma in the Dallas metroplex area under the supervision of Dr. Paul Pepe, Director of Emergency Medical Services at UT Southwestern Medical Center and Parkland Hospital, Dallas.
George Buchanan, MD, Professor, Department of Pediatrics, Children's Cancer Fund Distinguished Chair in Pediatric Oncology and Hematology
Michael DiMaio, MD, Associate Professor, Department of Cardiothoracic Surgery
Nilda Garcia, MD, Associate Professor, Department of Surgery, Pediatric Surgery
Steve Kernie, MD, Associate Professor, Department of Pediatrics and Center for Developmental Biology, Director of Pediatric Critical Care Residency Program
Edward Livingston, MD, Professor, Department of Surgery, Dr. Lee Hudson - Robert R. Penn Chair in Surgery
Christopher Yu-Hua Lu, MD, Professor, Department of Internal Medicine, Medical Director, Renal Transplantation
George McCracken, Jr., MD, Professor, Department of Pediatrics, The Sarah M. and Charles E. Seay Chair in Pediatric Infectious Diseases, GlaxoSmithKline Distinguished Professorship in Pediatric Infectious Diseases
Joseph Minei, MD, Professor of Surgery, Director of Parkland Memorial ICU
Paul E. Pepe, MD, Professor, Department of Surgery, Chairman Division of Emergency Medicine, Riggs Family Chair in Emergency Medicine
Pablo Sanchez, MD, Professor, Department of Pediatrics
James Valentine, MD, Professor and Vice Chairman, Department of Surgery, Frank H. Kidd, Jr., Distinguished Professorship in Surgery, Director of Surgical Residency Program
William Elliot Johnston, M.D., Margaret Milam McDermott Distinguished Chair in Anesthesiology and Pain Management
Gary Purdue, MD, Professor, Department of Surgery, Department of Surgery, Burns, Trauma and Critical Care
