A balanced blend of investigators, female and male, clinical and basic scientists with MD and/or PhD training, and diverse research expertise participate as training faculty in this program to sustain overlapping investigative themes and to foster group mentoring goals and the use of multidisciplinary approaches by our trainees. These general themes in this training program are highly relevant to the pathophysiologic events that occur during the development and/or complications of cardiovascular disease. Training faculty include:

Training Faculty and Investigative Themes


Investigative Theme

Primary Departmental

Training Faculty Affiliation Role
Inflammation, Cell Injury, and Adaptation
Greg J. Aune, MD/PhD Pediatrics Preceptor
Jean C. Bopassa, PhD Physiology Preceptor
Robert A. Clark, MD Medicine Preceptor
Alfred L. Fisher, MD/PhD Medicine/Geriatrics Preceptor
Paul F. Fitzpatrick, PhD Biochemistry Preceptor
Jun Hee Kim, PhD Physiology Preceptor
Linda M. McManus, PhD Pathology Preceptor
Jason R. Pugh, PhD Physiology Preceptor
W. Brian Reeves, MD Medicine/Nephrology Preceptor
Paula K. Shireman, MD Surgery Preceptor
Manjeri Venkatachalam, MD Pathology Preceptor
Carie Boychuk, PhD Physiology Preceptor
Ralph A. DeFronzo, MD Medicine/Diabetes Preceptor
Lily Q. Dong, PhD Cellular/Structural Biology Preceptor
Yves C. Gorin, PhD Medicine/Nephrology Preceptor
Balakuntalam Kasinath, MD Medicine/Nephrology Preceptor
Feng Liu, PhD Pharmacology Preceptor
Nicolas Musi, MD Medicine/Diabetes Preceptor
Cardiovascular Pathophysiology
Laura Cox, PhD Genetics Preceptor
Timothy Q. Duong, PhD Ophthalmology Preceptor
Marc D. Feldman, MD Medicine/Cardiology Preceptor
Hai-Chao Han, PhD Biomedical Engineering Preceptor
James D. Lechleier, PhD Cellular and Structural Biology Preceptor
Naomi L. Sayre, PhD Neurosurgery Preceptor
Mark S. Shapiro, PhD Physiology Preceptor
James D. Stockand, PhD Physiology Director / Preceptor
Glenn M. Toney, PhD Physiology Associate Director / Preceptor


Training Faculty Research Profiles.

Gregory J. Aune, MD, PhD, Pre-clinical Models of Chemotherapy-induced Delayed Cardiac Disease. It is estimated that by the year 2020, there will be over half a million long-term survivors of pediatric cancer living in the United States.  While cured of their disease, these patients have a substantially elevated risk of developing life-threatening health problems. Pediatric cancer therapy is definitively linked to late health effects such has secondary cancer, cardiovascular disease, endocrinopathies, metabolic syndrome, and pulmonary dysfunction; approximately 60% of childhood cancer survivors will die or develop a life-threatening health condition by age 50. Because of the extended latent period, clinical studies have focused on epidemiologic outcomes, development of treatment guided screening recommendations, and identification and management of health effects. Thus, there is a knowledge gap in understanding how different chemotherapy agents affect normal organs through mechanisms that ultimately manifest as dysfunction and disease decades later. The overall goal of Dr. Aune’s laboratory program is to develop pre-clinical models to study the cellular and molecular mechanisms that drive the development of late health effects.  Thus, he has established a mouse model of early anthracycline exposure to study the gradual development of heart failure.  Present efforts are designed to (1) Elucidate the molecular mechanism by which doxorubicin stimulates collagen production by cardiac fibroblasts and leads to myocardial fibrosis over time; (2) Evaluate the functional changes in vascular endothelium induced by early anthracycline exposure and identify the molecular mechanisms that lead to vascular dysfunction in survivors, and (3) Develop pre-clinical assays using cardiac fibroblasts to conduct high-throughput screens and identify candidate therapeutic approaches that block anthracycline-induced fibrosis. Collectively, these research areas provide numerous opportunities for postdoctoral research training. Dr. Aune’s research program also allows postdoctoral trainees an opportunity to interact with experts in cardiovascular science, clinical childhood cancer survivorship, and childhood cancer national/international advocacy.

Jean C. Bopassa, PhD, Novel Mechanisms in Estrogen-Dependent Cardioprotection following Ischemia Reperfusion Injury.  Dr. Bopassa’s long term research goal is to investigate the mechanisms involved in sex hormone cardioprotection against ischemia/reperfusion injury. His central hypothesis is that acute post-ischemic activation of estrogen receptors confers cardioprotective effects against ischemia/reperfusion injury by activating pro-survival signaling pathways leading to reduction of post-translational modifications of mitochondrial proteins resulting in the inhibition of the mitochondrial permeability transition pore (mPTP) opening, a key event in cell death after ischemia/reperfusion. Recently, he observed that acute pre-ischemic estrogen-induced cardioprotection against ischemia/reperfusion injury was primarily mediated via G protein-coupled estrogen receptor 1 (GPER1). His present investigations focus on whether acute post-ischemic estrogen treatment can also induce cardioprotective effects viaGPER1 in the intact animal. Male and ovariectomized female mice are subjected to left anterior descending artery occlusion followed by reperfusion. An estrogen bolus is delivered via the femoral vein before reperfusion and a GPER1 antagonist is given before estrogen administration. Myocardial infarct size and mitochondrial Ca2+ retention capacity required to induce mPTP opening are assessed after reperfusion. Expression of ubiquitinylated or acetylated calpains 1 and 10 is measured by Western Blot in mitochondrial and cytosolic fractions. Dr. Bopassa’s research program also allows the postdoctoral trainee an opportunity to interact with a variety of disciplines via active collaborations with Drs. Toney and Aune.

Robert A. Clark, MD, Oxidative Stress Associated Cell Signaling in Host Defense and Disease.  Dr. Clark has an extensive background of 30 years in basic research relevant to human diseases. His major focus has been on mechanisms of the inflammatory response and the cell biology and biochemistry of human phagocytic cells, ranging from studies of neutrophil function and clinical disorders to in-depth molecular analyses of cellular components involved in the killing of invading microorganisms and the regulation of their expression and function. Dr. Clark’s laboratory studies neutrophil signal transduction and activation at cellular and molecular levels, focusing particularly on the respiratory burst NADPH oxidase, a multi-component enzyme responsible for much of the microbicidal capability of phagocytic cells through the stimulus-dependent formation of reactive oxygen species (ROS). Recombinant proteins are used to determine the mechanisms of enzyme activation, considering phosphorylation, translocation of cytosolic components to membranes, role of SH3 domains, and the function of the rac GTPases. The overall goal is to understand at a molecular level the cellular responses that result in microbial killing and tissue injury. An area of increasing interest focuses on a family of genes (NOX) that are homologous to the neutrophil oxidase, but are expressed in many non-myeloid cells where they are involved in signaling, cell growth, aging, and host defenses. The lab is exploring the role of these oxidases in transcriptional regulation of genes that are relevant to chronic inflammation, the biology of aging, and to the host response to invading microorganisms. Of rapidly increasing prominence in Dr. Clark’s program are the oxidative stress-associated cellular signaling and injury pathways involved in degenerative diseases of the vascular system. Trainees working in this laboratory will learn a broad range of basic concepts and techniques in biochemistry, molecular biology, and cell biology. They will be engaged in projects dealing with the mechanisms of generation of ROS by the NOX family of NADPH oxidases, as well as the functional roles of these products of oxygen metabolism, emphasizing oxidative stress and degenerative diseases.

Laura Cox, PhD, Genetics of Cardiovascular DiseaseFor more than two decades Dr. Cox has conducted genetic and genomic research using the baboon as a model of cardiovascular disease. In addition, due to the lack of commercial molecular genetic and genomic reagents for baboon research, Dr. Cox has been centrally involved with the development of genetic and genomics tools, and bioinformatic methods for nonhuman primate research. Dr. Cox developed an analysis pipeline that uses an iterative approach with multiple reference genomes to annotate genome sequences for species with a poorly annotated reference genome or without a reference genome. This pipeline has also been optimized for nonhuman species such sheep, opossum and rat. As part of these research projects and resource development, Dr. Cox has managed research teams for analysis of large datasets from complex pedigrees, and collaborated with scientists with varying expertise for application of results from these studies. These methods and tools have been essential for molecular genetic and genomic studies in baboon for CVD and other complex diseases.

Ralph A. DeFronzo, MD, Pathophysiological Alterations in Type 2 Diabetes Mellitus (T2DM).  The major focus of Dr. DeFronzo’s research has been (1) examination of the cellular mechanisms by which insulin promotes  glucose uptake and metabolism in healthy subjects and (2) definition of metabolic, biochemical, and molecular basis of impaired insulin action in obese nondiabetic and type 2 diabetic individuals, in the normal glucose tolerant offspring of two diabetic parents, in patients with a variety of endocrinopathies, and in subjects with the insulin resistance syndrome, (3) the role of mitochondrial dysfunction in the development of insulin resistance; (4) the relationship between insulin resistance and the development of atherosclerotic cardiovascular disease; (5) the role of lipotoxicity and glucotoxicity in the pathogenesis of type 2 diabetes; (6) elucidation of the genes responsible for type 2 diabetes.  These studies have been carried out in both man and animals and have involved a variety of techniques including: (a) muscle biopsy; (b) novel isotopic methodologies developed in his laboratory; (c) forearm and leg catheterization; (d) indirect calorimetry; (e) insulin/hyperglycemic clamps; (e) biochemical, enzymatic, and isotopic determinations on tissue (muscle, adipose, liver) samples; (f) molecular analysis of the glucose transporter and hexokinase genes and their expression/function in muscle; (g) molecular and biochemical analysis of the insulin receptor signal transduction system (IR and IRS-1 phosphorylation; p85 and PI3 kinase activity associated with IRS-1; total PI3-kinase activity); (h) quantitation of muscle/liver/abdominal fat content by MRI/MRS; (i) measurement of muscle ATP synthesis by MRS; (j) measurement of mitochondrial function using confocal laser microscopy and enzymatic activity assays. These techniques allow in vivoand in vitro quantitation of glucose transport, phosphorylation, and oxidation, glycolysis, glycogen synthesis, muscle enzyme activity (hexokinase, glycogen synthase/phosphorylase, pyruvate dehydrogenase), insulin signaling, hepatic glucose production, and gluconeogenesis.  By contrasting measurements performed in diabetic and obese patients with those in healthy controls, the specific intracellular disturbances responsible for insulin resistance (both peripheral and hepatic) in these common clinical disorders have been delineated. The specific contributions of chronic hyperglycemia (“glucose toxicity”) and chronic hyperinsulinemia to the observed defects in insulin action and insulin secretion in type 2 diabetes have also been explored; observations in this area have yielded novel and innovative approaches to the treatment of type 2 diabetes. In all of the above, there are ample opportunities for clinically-based postdoctoral research training, an especially relevant issue for physicians who desire a well-founded program in the basic mechanisms of occlusive vascular disease

Lily Q. Dong, PhD, Adiponectin Receptor-Mediated Intracellular SignalingThe major focus of Dr. Dong’s research is on the identification of alterations that contribute to insulin resistance, a primary contributing factor in the pathogenesis of type 2 diabetes. This condition (characterized by the loss of insulin sensitivity in tissues) results in an impairment of glucose uptake in skeletal muscle and fat cells, and an uncontrolled production of glucose in hepatic cells; all of these events contribute to increase glucose levels within the bloodstream. Adiponectin or Acrp30 is secreted by adipose tissue and released into the bloodstream where it serves as an insulin sensitizer.  The serum concentration of adiponectin is significantly reduced in type 2 diabetic and obese patients. Since adiponectin enhances insulin sensitivity, it has the potential to be used therapeutically in the treatment of type 2 diabetes and obesity. However, the molecular mechanism governing adiponectin action is largely unknown. Dr. Dong’s group has identified APPL1, an adaptor protein with multiple function domains, as the first signaling molecule with immediate binding to adiponectin receptors, and positively mediating adiponectin signaling in muscle cells in vitro and in vivo. In addition, she has shown that APPL2, an isoform of APPL1, negatively regulates adiponectin signaling. She proposed that APPL1/APPL2 isoforms function as an integrated “Yin-Yang” regulator in adiponectin signaling. Recently, her laboratory has demonstrated that APPL1 mediates the insulin sensitizer role of adiponectin by facilitating the binding of IRS1/2 to the insulin receptor in response to adiponectin stimulation.  These findings provide potential mechanisms behind insulin resistance and the development of type 2 diabetes.  Dr. Dong’s laboratory provides a rich research training environment for early career scientists to acquire state-of-the art skills relevant to the development of interventions for improved insulin sensitivity in diabetes.

Timothy Duong, PhD, Stroke Imaging and Diabetic Retinopathy. Dr. Duong’s research encompasses several areas including: Stroke Imaging. Stroke remains the third leading cause of death and the leading cause of long-term disability.Dr. Duong previously established a rat stroke model with reproducible perfusion-diffusion mismatch (which approximated the ischemic penumbra), and developed and applied quantitative perfusion, diffusion MRI and analysis methods to characterize pixel-by-pixel the spatiotemporal progression of diffusion and perfusion characteristics under different middle cerebral artery occlusion (MCAO) durations in the acute phase. Imaging measures were compared with histology. Dr. Duong now seeks to develop novel multimodal MRI approaches to probe the “physiological” and “functional” characteristics of the ischemic tissue at risk in stroke rats. These studies will focus on using blood-oxygenation-level dependent (BOLD) and cerebral blood flow (CBF) fMRI of physiologic challenge (hypercapnic and oxygen) and functional activity (stimulation and resting state) to probe perfusion and diffusion abnormality at 7 Tesla. He uses these methodologies to study acute and chronic stroke. Together, through an artificial neural-network predictive model, he is examining different MRI measures to accurately predict acute infarction and chronic recovery. His central hypothesis is that through improved understanding of the physiological and functional profiles of ischemic tissue at risk and their spatiotemporal characteristics, tissue viability and functional recovery can be accurately predicted using only acute MRI data.

Marc D. Feldman, MD, Optical Coherence Tomography to Identify Macrophages in Vulnerable Plaque.  Dr. Feldman’s long term goal is to diagnose and treat vulnerable plaque to prevent heart attacks and strokes in patients using Optical Coherence Tomography (OCT). OCT utilizes near-infrared light to provide a structural image similar to histology with a resolution of 4 μm (greater than other competing structural imaging technologies such as ultrasound, MRI, and CT).  Since vulnerable fibrous caps which rupture and cause heart attacks  and strokes in patients are all less than 65 μm (average = 32 μm), OCT has the resolution to identify these thin fibrous caps, as well as to image large lipid cores beneath, which, if they occupy greater than 40% of the mass of the arterial wall, also make the plaque vulnerable for rupture.  Unique to Dr. Feldman’s  program is extending OCT to perform in vivo cellular imaging.  Macrophage infiltration into the “shoulders” of the fibrous cap is also a high risk feature for plaque rupture.  Intravenously injected gold nanoparticles coated with dextran (which are small enough, i.e., <40 nm, to avoid significant uptake by the liver and spleen to extend their time in the circulation) interact with the dextran receptor of tissue macrophages and are engulfed. These gold nanoparticles in plaque-based macrophages can be stimulated with two photon luminescence and their presence detected. The application of pulsed laser can also selectively heat and injure these nanoparticle-laden macrophages.  This approach is being used to test the hypothesis that vulnerable plaque can be identified and stabilized to prevent rupture in apoE -/- atherosclerotic mice and balloon-injured, fat fed atherosclerotic New Zealand White rabbits. In these studies, there are numerous opportunities for fundamental postdoctoral research training. Dr. Feldman’s research program allows the postdoctoral trainee an opportunity to interact with a variety of disciplines via an active collaboration between Biomedical Engineers (Thomas Milner, PhD) and Chemical Engineers (Keith Johnson, PhD) at the University of Texas at Austin, and physician-scientists at the University of Texas Health Science Center in San Antonio.

Alfred L. Fisher, MD PhD, Metabolic Stress, Altered Proteasomal Function, and Tyrosine Degradation. Dr. Fisher’s studies are designed to define how aromatic amino acids influence cell signaling pathways to control insulin-sensitivity and the activation of the innate immune system. Currently, his work in this area focuses on the hypothesis that the free amino acid, tyrosine, binds to a cell surface G-protein coupled receptor to promote changes in the AMP kinase and p38 kinase signaling pathways. Research in his lab uses the nematode, C. elegans, cell culture experiments involving human and rodent cell lines, and also in vivo models (mouse). This combined approach allows the lab to readily move from genetic and RNAi experiments to biochemical experiments and in vivo physiologic studies. Dr. Fisher’s laboratory offers diverse, multidisciplinary training opportunities for postdoctoral research fellows.

Paul F. Fitzpatrick, PhD, Flavoproteins and Nonheme Iron Enzymes. The Fitzpatrick laboratory studies the mechanisms of catalysis and regulation of the enzymes, tyrosine hydroxylase (the rate-limiting enzyme for catecholamine biosynthesis), phenylalanine hydroxylase (deficiencies in which lead to the progressive neurodegenerative disease, phenylketonuria), and tryptophan hydroxylase (the rate-limiting enzyme in serotonin biosynthesis). He utilizes a combinational of functional and structural approaches, from NMR spectroscopy to rapid-reaction kinetics. He has determined the catalytic mechanisms of all three enzymes. Thus, he established that regulation of tyrosine hydroxylase involves feedback inhibition by catecholamines counterbalanced by phosphorylation of Ser40 by protein kinase A. He determined that inhibition involves an interaction between the catecholamine bound in the active site and the N-terminus of the regulatory domain. Phosphorylation disrupts this interaction, opening up the active site. His laboratory recently determined the structure of the isolated regulatory domain of the enzyme, allowing the proposal of a model for the intact protein for the first time. He is also studying the conformational changes that occur upon allosteric activation of phenylalanine hydroxylase and the effects of PKU-causing mutations. He has shown that the conformational change upon binding of phenylalanine to the regulatory domain results in dimerization of the regulatory domains from adjacent subunits and that PKU mutants that disrupt dimerization of the regulatory domains disrupt the allosteric activation of the enzyme. Sophisticated biochemical techniques and rigorous training is available to postdoctoral research trainees in Dr. Fitzpatrick’s laboratory.

Yves Gorin, PhD, Sources of Oxygen Radicals as Novel Therapeutic Targets for the Treatment of Diabetic Kidney DiseaseDr. Gorin’s research aims to identify and characterize sources of oxidants in order to design new therapeutic interventions to prevent diabetic kidney disease. He has made significant and seminal contributions in identifying Nox4 (NADPH oxidase 4) as a source of reactive oxygen species (ROS) in mitochondria and as a central mediator of diabetic complications in the kidney and the heart using experimental animal models of diabetes. Dr. Gorin is familiar with rodent models of diabetes, assessment of renal and cardiac function and evaluation of structural abnormalities in the kidney and heart as well as with techniques examining signal transduction pathways and redox mechanisms involved in renal and vascular cell injury. His group provided evidence that Nox4-dependent endothelial nitric oxide synthase (eNOS) dysfunction is critical for diabetes-induced renal cell injury. He also unveiled the protective function of Sestrin 2/AMP-activated protein kinase (AMPK) signaling pathway as a suppressor of Nox4 activity in the diabetic environment. Dr. Gorin contributed to the identification of AMPK and mammalian target of rapamycin complex 1 (mTORC1) pathway as upstream modulators of Nox4 in renal and vascular cell injury. Recent studies in his laboratory also revealed that Nox4 is controlled at the translational level by mammalian target of rapamycin complex 2 (mTORC2) and mRNA binding protein HuR in the context of diabetes. Collectively, these studies are opening a promising avenue for the design of rational therapy. Finally, Dr. Gorin has recently embarked on the investigation of the role of Duox1 and Duox2 NADPH oxidases in the pathogenesis of diabetic nephropathy. He participates in preclinical studies that test the ability of dual Nox1/4 pharmacological inhibitors to preserve renal and cardiac function in experimental animal models of diabetes; phase I safety studies in healthy subjects and phase II clinical trials in patients with type diabetic nephropathy have been completed and are encouraging. Dr. Gorin has also initiated translational studies using samples from diabetic patients with kidney disease to establish that the molecules described above can be used as biological markers in order to facilitate the design of more advanced approaches to diagnose diabetic nephropathy and the other diabetic complications. In all, there are vast opportunities for fundamental postdoctoral research training. Dr. Gorin’s research program allows postdoctoral trainees opportunities to interact with PhD scientists and physician scientists at UTHSCSA.

Hai-Chao Han, PhD, Arterial Tortuosity and Diastolic Heart Failure. Dr. Han’s cardiovascular biomechanics laboratory studies vascular wall remodeling in tortuous arteries and diastolic compliance in diastolic heart failure. Tortuous blood vessels are commonly seen in the aorta, carotid, iliac, cerebral, retinal, coronary, and peripheral arteries and veins. They are associated with aging, hypertension, and atherosclerosis but the mechanisms remain unclear. The long term goal of Dr. Han’s laboratory is to elucidate the biomechanical mechanisms of the development of vessel tortuosity and to develop new techniques to treat and prevent these vascular diseases. Another area of research in Dr. Han’s lab focuses on the surgical treatment of left ventricular hypertrophy and diastolic heart failure. Reduced left ventricular diastolic compliance is a feature of heart failure with preserved ejection fraction (HFpEF), which is responsible for half of all heart failure hospitalizations and is increasing in prevalence each year. In collaboration with Dr. Marc Feldman in Cardiology, Dr. Han’s lab strives to develop a surgical technique to increase left ventricular compliance to treat diastolic heart failure. Experimental, computational and theoretical modeling approaches are integrated in these studies. The ultimate goals are to better understand adaptation in the cardiovascular system and to improve treatment of cardiovascular diseases.

Balakuntalam Kasinath, MDRenal Cell and Molecular Changes During Aging.  The main objective of investigation in the Kasinath lab is to understand the molecular and cell biologic mechanisms of kidney fibrosis which commonly leads to functional decline culminating in end stage kidney disease. Diabetes is the most common cause of end stage kidney disease. Aging is associated with progressive loss of nephrons in the absence of disease. The hallmark of kidney injury in diabetes and aging is fibrosis. We employ both kidney cells grown in culture and mice some of which are genetically altered. We study cellular processes that regulate the synthesis of proteins including extracellular matrix proteins that contribute to kidney fibrosis; the studies address signaling mechanisms that control the transcription and mRNA translation of specific proteins involved in fibrosis. We have recently identified endogenously produced hydrogen sulfide as an important regulator of protein synthesis in the kidney in the setting of diabetes and aging. We aim to identify interventional methods that target molecules such as hydrogen sulfide to ameliorate kidney injury in diabetes and aging. Our research program provides ample opportunities for the trainee to interact with several independent investigators in the fields of cell biology (Dr. G. Ghosh Choudhury, UTHSCSA) and aging (Drs. Nelson and Strong, Barshop Institute, UTHSCSA).

James Lechleiter, PhD, Molecular and Cellular Mechanisms of Neuroprotection during Ischemia, Brain Injury, and Neurodegeneration. Research in Dr. Lechleiter’s laboratory is focused on the molecular and cellular mechanisms of neuroprotection that occur in response to ischemic stress, acute brain injury and aging.  Sophisticated technologies employ in vitro and in vivo strategies. A major emphasis is on the potential of astrocytes as a novel therapeutic target for the treatment of brain injuries.  Astrocytes are known to play a crucial role in supporting and protecting neuronal function and in modulating brain energy metabolism.  One research project is an investigation of the underlying protective mechanisms mediated by stimulation of the purinergic P2Y1 receptor.  A second major research project is directed towards understanding the neuroprotective efficacy of thyroid hormones via stimulation of fatty acid oxidation.  A third area of research is focused on the long-term neurological consequences of repetitive traumatic brain injury (rTBI).  Finally, Dr. Lechleiter’s laboratory is investigating the role of ER stress and the unfolded protein response (UPR) immediately after brain injuries as well as in the development of age-associated neurological deficits. Thus, diverse research training opportunities exist within Dr. Lechleiter’s laboratory.

Feng Liu, PhD, Signal Transduction and Regulation in Metabolism and AgingA primary investigative focus of Dr. Liu is the signal transduction pathways involved in the regulation of many important metabolic processes such as glucose uptake and glycogen synthesis. He focuses major efforts on the insulin, mTORC1, and adiponectin signaling pathways. Defects in these signaling cascades can result in insulin resistance, one of the primary contributors to the development of type 2 diabetes. Molecular biology, biochemistry, and cell biology approaches as well as animal models are used to define the molecular mechanism of insulin signal transduction and insulin resistance, and to identify and characterize signaling components involved in these signaling processes. Better understanding of the signaling components involved in mediating insulin, adiponectin, and mTORC1 signal transduction will generate information that may contribute to the development of new therapeutic strategies for the treatment of type 2 diabetes. Dr. Liu’s laboratory provides an excellent scientific environment for multidisciplinary postdoctoral training and established collaborations with many outstanding research teams throughout the university for the study of diabetes and aging. Back to top

Nicolas Musi, MD, Intracellular Signaling Alterations in Insulin Resistant Skeletal Muscle.  Dr. Musi has a robust research program in metabolic/endocrine gerontology, devoted to exploring the effects that aging has on numerous metabolic and cellular processes. His research program involves a combination of human, animal, and cell culture approaches to tackle questions related to the molecular biology of insulin resistance and sarcopenia in diabetes and aging.  Particular emphasis has been placed on determining the effect of major signal transduction pathways on mitochondrial function, glucose and lipid metabolism in older and diabetic subjects. This includes delineating the role of inflammatory pathways on mitochondrial function and glucose and lipid metabolism in older and diabetic subjects as well as understanding the role of inflammatory signaling pathways (NFkB) and mitochondrial dysfunction in the pathogenesis of insulin resistance and sarcopenia in older adults.  He also explores whether the AMPK-PCG1 signaling axis is involved in the age-related changes in mitochondrial function and lipid metabolism that occur in older adults. Dr Musi is an active educator and research mentor; he supervises and mentors geriatrics and endocrinology clinical and basic research fellows, residents, and graduate students; he provides a robust postdoctoral research training environment.

Jason Pugh, PhD,  A fundamental question in neuroscience is how neurons receive, process, and transmit signals, transforming sensory input to behavioral output. At the cellular level, neurons transmit signals and store information primarily through synaptic connections between neurons. Synapses are remarkably diverse in the transmitters used, receptors express (both pre- and postsynaptic), kinetics, and ability to undergo short-term and long-term changes in strength. Each of these properties influences how information is transmitted and stored at a particular synapse. We are interested in understanding how synaptic properties are fine-tuned to function within specific circuits and process information.To address these questions, we work on synapses in the cerebellar circuit, a brain region primarily involved in motor learning and motor coordination (though involvement in cognitive functions have also been demonstrated). We study synaptic transmission in the cerebellar circuit because the underlying neural circuity is relatively simple and highly regular throughout the cerebellum, making it possible to correlate synaptic properties with specific circuit functions and even behavioral output. We primarily use patch clamp electrophysiology, to measure postsynaptic currents and potentials, and two-photon calcium imaging, to measure pre- or postsynaptic calcium influx and cell morphology. Our lab is currently focused on two projects:1. Function of presynaptic GABAA and GABAB receptors. Parallel fiber synapses (the primary excitatory synapses in the cerebellum) express GABAA and GABAB receptors in their presynaptic boutons. Previous work has shown that GABAA receptors enhance release of neurotransmitter while GABAB receptors inhibit release of neurotransmitter. However, these two receptors are activated by the same ligand (GABA) and are therefore likely to be co-activated in vivo. Do the opposing effects of these receptors cancel one another out? Does one receptor effect dominate over the other? Or do differences in the kinetics and affinities of these receptors allow them to be selectively activated in some conditions? 2. Role of dystrophin in cerebellar function. Muscular dystrophy is caused by mutations in the gene for dystrophin, a protein highly expressed in muscle tissue that acts as a linker between the intracellular cytoskeleton and the extracellular matrix. Dystrophin is also expressed in the central nervous system and many individuals with muscular dystrophy show cognitive deficits, suggesting dystrophin may also play a role in neuronal function. Dystrophin is most highly expressed in Purkinje cells of the cerebellum, specifically at inhibitory synapses onto these cells. We hypothesize that dystrophin mutations disrupt cerebellar function which contributes to the loss of motor and cognitive function observed in muscular dystrophy. We are addressing these questions using patch-clamp electrophysiology to measure synaptic function and firing in the cerebellar circuit of mouse models of muscular dystrophy and creating a Purkinje cell specific knock-out of dystrophin for behavioral testing.

W. Brian Reeves, MD, Inflammation and Ion Channels in Acute Kidney Injury (AKI), and TNF in Diabetic Nephrophathy.  Dr. Reeves’ research focuses on understanding the role of TNF and ion channels in inflammatory renal injury.  He is specifically interested in understanding aberrant cell signaling that leads to injury and progression of renal pathology.  His program uses a multidisciplinary approach involving human studies, whole animal studies and genetic manipulation, as well as detailed biochemical and molecular biological assessment of injury and cell signaling. Dr. Reeves has demonstrated that TNF is elevated in experimental models of cisplatin nephrotoxicity and that inhibition or deletion of TNF reduced kidney injury. His lab determined that TNF signals primarily via TNFR2 and subsequent p38 MAPK activation to produce toxicity. Moreover, the source of TNF was shown to be parenchymal cells rather than leukocytes, and that TLR4 on renal parenchymal cells was critical for cisplatin-induced TNF production and kidney injury.  Using a diphtheria toxin depletion model, Dr. Reeves found that dendritic cells had an anti-inflammatory action and protected against cisplatin AKI; and that production of IL-10 by dendritic cells accounted for some of this anti-inflammatory action. Inflammation is recognized to play a role in diabetic nephropathy, but the mediators of this process are still being defined. Dr. Reeves has performed animal studies to examine the role of TNF as a mediator. He determined that the production of TNF is increased in diabetic mice subjected to ischemic injury and that this exuberant production of TNF is responsible for the increased susceptibility of diabetic mice to ischemic injury. Using TNF deficient mice and TNF neutralizing antibodies, Dr. Reeves demonstrated that TNF is an important mediator of diabetic nephropathy.  Moreover, with conditional knockouts of TNF developed in his laboratory, Dr. Reeves determined that macrophages are a key source of TNF within diabetic kidneys. This work forms the basis for proposed studies to examine the effects of TNF antagonists on diabetic nephropathy in humans.

Naomi Sayre PhD, Cholesterol Homeostasis and Neuroprotection during Stroke. Dr. Sayre’s laboratory is interested in the processes that affect brain repair and recovery after injury, with particular emphasis on the role that cholesterol homeostasis plays in these processes after stroke. Astrocytes are the primary supportive cells in the brain and also regulate cholesterol homeostasis, and so have unique potential to affect recovery after brain damage due to stroke. Astrocytes secrete apolipoprotein E (ApoE), and in humans, 3 alleles exist (E2, E3, and E4). ApoE4 is associated with poor recovery after stroke and traumatic brain injury, particularly in the long term after damage. In the brain, the main clearance receptor for ApoE4 is LRP1 (low-density lipoprotein receptor related protein 1). LRP1 promiscuously binds and removes several extracellular ligands and receptors from the plasma membrane via receptor-mediated endocytosis. Dr. Sayre hypothesizes that ApoE4 differentially interacts with LRP1 compared to ApoE3. This differential interaction is expected to result in greater competition for LRP1 function, thereby resulting in a decreased ability of LRP1 to remove extracellular ligands and receptors. Dr. Sayre seeks to determine if ApoE4 increases sensitivity to cell death after stroke by competing for inflammatory receptor clearance by LRP1. In vascular cells, LRP1 has been shown to influence the quantity of the TNFα receptor on the plasma membrane. Dr. Sayre hypothesizes that in the brain, ApoE4 prevents removal of TNFα receptor by LRP1, thereby conferring increased sensitivity to cytokines such as TNFα. Such sensitivity is expected to result in greater-long term damage after stroke or traumatic brain injury. Dr. Sayre will test this hypothesis with a combination of cell-culture models and in vivo mouse models of stroke and traumatic brain injury; she plans to utilize floxed-LRP1 mice to generate astrocyte-specific LRP1 knock outs.

Mark S. Shapiro, PhD, Modulation and Functional Role of Ion Channels in Excitable Cells. The research program of Mark Shapiro spans the physiology, modulation and role in disease of a variety of ion channels in neurons, cardiomyocytes and non-excitable cells, with particular emphasis on voltage-gated K+ and Ca2+ channels. Most of the projects in this laboratory center on “M-type” (KCNQ) K+, and Ca2+ channels, and signaling pathways of Gq/11-coupled receptors, using patch-clamp electrophysiology of native neurons and heterologous systems, biochemistry, confocal and TIRF microscopy, molecular biology and live single-cell and whole-animal imaging. Dr. Shapiro also uses STORM super-resolution nanoscopy to probe the multi-protein complexes underlying modulation of ion channels in a variety of cell types. In addition, he is systematically exploring the role of the scaffolding/regulatory protein, A-kinase anchoring protein (AKAP)79/150 in orchestrating transcriptional and regulatory control of M/KCNQ channels in sympathetic and nodose sensory neurons, in the brain, and in smooth muscle. He has documented the PIP2 sensitivity of many types of channels to the regulatory lipid, phosphatidylinositol 4,5-bisphosphate (PIP2), the mechanisms and structural determinants of receptor-mediated suppression of M currents and Ca2+ currents, the modulation of KCNQ channels by calmodulin, AKAPs and Src kinase, the roles of M channels in airway smooth muscle, and in sensory neurons. Besides these channels, his laboratory is also studying the mechanisms of regulation and organization of pain-sensing TRPV channels, Ca2+-activated TMEM16/Ano channels and other channels critical to sensation, mood, airway and cardiovascular function.
Although Dr. Shapiro’s laboratory is primarily involved in basic-science, he also devotes effort to translational projects. Thus, he is investigating novel strategies to prevent acquired epilepsies and the role of M channel regulation at the acute and transcriptional levels in epileptogenesis. Additionally, he also is exploring novel and provocative roles of M/KCNQ channels as a neuroprotective mechanism to prevent brain damage during cerebrovascular ischemic stroke and traumatic brain injury; the latter studies involve other researchers in San Antonio at three different institutions. Finally, he is engaged in novel molecules to treat asthma and other airway and cardiovascular diseases.

Paula K. Shireman, MD, Inflammation in Collateral Artery Formation, Angiogenesis, and Skeletal Muscle Regeneration. Dr. Shireman’s research is focused on inflammatory- mediated mechanisms of collateral artery formation, angiogenesis and skeletal muscle regeneration. Her lab utilizes various mouse models of muscle injury including femoral artery excision (ischemic injury) and cardiotoxin injection (toxic injury). Using these models, Dr. Shireman’s laboratory has documented that mice lacking monocyte chemotactic protein-1 (MCP-1) or its receptor, CC chemokine receptor-2 (CCR2), have impaired angiogenesis and skeletal muscle regeneration despite enhanced expression of muscle-specific transcription factors and an associated increase in intramuscular adipocytes after injury. Interestingly, female mice develop increased adipocytes in the area of injury compared to male animals; these observations suggest a hormonal influence on the processes leading to skeletal muscle regeneration following injury. Further, she has observed that old mice with sarcopenia retain their ability to regenerate muscle after severe injury suggesting that satellite cell dysfunction was not the cause of sarcopenia. Current research is focused on how microRNAs play major roles in macrophage polarization and stem cell proliferation and differentiation. Studies to understand the regulatory role microRNAs on muscle regeneration, angiogenesis and macrophage polarization are underway. Routine techniques include transfections, real time PCR, miRNA arrays, flow cytometry, cell sorting, isolation and culture of myogenic progenitor cells and macrophages, confocal microscopy, histomorphometry, biochemical assays, laser Doppler imaging, and microvascular surgery. All of these models are designed to provide a better understanding of the pathophysiologic mechanisms that regulate angiogenesis during reparative events following tissue injury.  Dr. Shireman also has a keen interest in understanding the long-term outcomes of vascular repairs secondary to trauma in military service members with mangled extremities and limb salvage compared to those with amputation. Given the broad scope of techniques and interests that are currently being pursued, there are a multitude of opportunities for training of postdoctoral research fellows.

James D. Stockand, PhD, Epithelial Ion Channels in Water Balance and Blood Pressure Control.  The primary focus of Dr. Stockand’s laboratory is in understanding the cellular and molecular mechanisms modulating the activity of epithelial ion channels, particularly the epithelial Na+ channel (ENaC). The structural relationship between the subunits that comprise ENaC is being defined, as well as mapping interactions between this channel and its regulatory proteins.  ENaC is a centrally positioned effector modulating systemic Na+ and water balance. Thus, the activity of this channel directly impacts blood pressure and epithelial hydration. Indeed gain of function mutations in ENaC and its upstream regulatory pathways lead to hypertension in humans, as well as to airway disease. In contrast, loss of function mutations in ENaC lead to salt wasting and hypotension and acute respiratory distress. Most hypertension is essential and associated with salt sensitivity. Thus, to fully understand the cellular basis of these diseases, it is essential to understand the control points regulating Na+ reabsorption, such as ENaC. Dr. Stockand has made significant contributions to understanding how ENaC is modulated by small G proteins, such as ras, rac and rho, and how phospholipid signaling effects channel gating. These results have directly implicated ras and phospholipid signaling in the transduction pathway whereby aldosterone stimulates ENaC leading to Na+ reabsorption in the distal nephron. Dr. Stockand’s laboratory uses a combination of experimental methodologies to investigate ENaC. This includes evanescent field fluorescence microscopy, electrophysiology, cell biology, genetics, molecular biology, biochemistry and in vivo measurements of blood pressure and Na+ excretion. His research interest in ion channels intersects many areas of biology and physiology.  For instance, understanding questions about channel proteins involved in Na+ transport across renal epithelial cells is informative about the role played by these proteins in the lung, gut, skin, brain and peripheral sensory tissue.  The reason for this is that key proteins and fundamental mechanisms are common to most epithelium: identifying the role of a channel in the kidney predicts its function in related tissue.  Moreover, many ion channels in the kidney are also common to neurons and sensory cells.  Thus, while his research program focuses on ion channels in the mammalian kidney, he also is interested in studies of related channels in sensory neurons, gut, and lungs.

Glenn M. Toney, PhD, Sympathetic Nervous System Function in the Regulation of Blood Pressure.  Dr. Toney’s laboratory investigates cellular, molecular and integrative mechanisms that regulate sympathetic nervous system function. Although sympathetic nerve activity (SNA) increases in states such as dehydration, salt-sensitive hypertension, and congestive heart failure (CHF), functional changes that occur among sympathetic-regulatory neurons of the brain to produce this exaggerated output remain poorly understood. Dr. Toney’s laboratory has helped to demonstrate that neurons in the hypothalamic paraventricular nucleus (PVN) are key contributors to the increase in SNA that accompanies water deprivation and acute body fluid hyperosmolality – stimuli that mimic the neurohumoral changes that occur in arterial hypertension and CHF. Thus, activation of SNA by central hyperosmolality is mediated by activation of type 1 (AT1) ANG II receptors in the PVN. In vitro patch clamp studies have established that AT1 receptors are located on presynaptic terminals of PVN neurons whose axons project to the rostral ventrolateral medulla (RVLM), a key sympathoexcitatory region of the brainstem. Upon activation by angiotensin II, presynaptic AT1 receptors promote release of glutamate to increase the discharge frequency of PVN-RVLM neurons.  Interestingly, the frequency of glutamatergic miniature excitatory postsynaptic currents is significantly increased among PVN-RVLM neurons in animals with established CHF compared to sham operated controls.  Thus, angiotensin II and glutamate could interact within the PVN to increase SNA in heart failure. Studies in whole animals have shown that AT1 receptors and ionotropic glutamate receptors (AMPA and NMDA) in the PVN are required for SNA to increase upon acute neuronal disinhibition produced by local GABA-A receptor blockade. Thus, excitation by angiotensin II and glutamate appears to counter GABA-induced inhibition of sympathetic-regulatory neurons in the PVN. Determining how the balance of these synaptic effectors is established/maintained to control SNA and the mechanisms by which this balance may be shifted to favor excitation is a major focus of current efforts.
Trainees in this laboratory learn techniques such as single neuron recording in vivo, whole-cell patch clamp recording in vitro, cell culture, cDNA transfection, brain microinjection, retrograde tracing, western blotting, genotyping, immunocytochemical staining, juxtacellular labeling, microiontophoresis, sympathetic nerve recording, and telemetric recording. The true value of these techniques can only be realized through an intimate understanding of the biology that drives scientific inquiry, an important goal for postdoctoral fellows.

Manjeri Venkatachalam, MDCell Injury and Cell Death in Acute Renal Failure.  Dr. Venkatachalam’s research career has spanned the gamut of the structural, physiological and biochemical basis for normal kidney function and its breakdown in disease, including in response to high blood pressure and diabetes. This has included a good deal of emphasis on the renal microvasculature: glomerular arterioles, peritubular capillary network and glomeruli. Current work in his laboratory is devoted to understanding how acute kidney injury (AKI) contributes to the progression of chronic kidney disease (CKD), eventuating in end stage renal disease. In his working hypothesis, AKI plays a role either as single incidents (or a limited number of episodes) of acute injury in the setting of CKD, or as multiple, serially occurring microscopically focal acute injury consequent to occlusive arteriolosclerosis and/or arteriolar spasm. Dr. Venkatachalam is testing these possibilities in CKD models with graded reductions of renal mass (mimicking the pathophysiology of CKD) and superimposed AKI, and in hypertensive models of CKD that exhibit occlusive arteriolosclerosis and microscopically focal acute damage. Dr. Venkatachalam believes that incomplete repair of tubule injury and impaired recovery of normal tubule structure results in a pathologically altered persistently undifferentiated tubule phenotype that exhibits phlogistic and profibrotic signaling, causing tubulointerstitial fibrosis. For severe and/or progressive tubulointerstitial fibrosis to occur, kidneys afflicted by CKD must suffer either massive AKI episodes usually caused by ischemia, or serial microscopically focal AKI caused by microvascular pathology. In either case, a hemodynamic/vascular defect is fundamental. He has established reproducible models of hypertensive and non-hypertensive CKD and ischemic AKI, and his studies are ongoing. Thus, kidney research in Dr. Venkatachalam’s laboratory is fundamentally related to vascular pathology and dysfunction, and his research would therefore provide an excellent platform for training in vascular disease.