Ion channel kinetics and structure; Membrane Transport (Ion Transport); Molecular and Cellular Biology; Neurobiology; Pathophysiology; Gene Expression; Signal Transduction
Neuronal firing patterns are highly diverse because neurons regulate a wide variety of different behaviors and physiological functions including cognition and memory. Whether a neuron exhibits regular spiking, burst firing, adaptation or high frequency firing will largely be determined by which specific ion channel genes a neuron chooses to express. I am interested in a class of potassium channels that are sensitive to intracellular sodium. There are two members in this family, known as Slack and Slick, and both channel subunits are expressed in many different types of neurons. I am particularly interested in how these channels contribute to the firing patterns of pain-sensing neurons and neurons of the cerebral cortex. Understanding when, where and how these channels are working should provide important information on sensory and cortical processing and will provide insights on nociception, psychiatric disorders such as schizophrenia and bipolar disorder and neurological diseases such as epilepsy.
Endocrinology, Diabetes and Metabolism; Neurodegenerative disorders; Pathophysiology; Endocrinology; Molecular Basis of Disease
Dr. Browne’s research is focused primarily on the clinical biochemistry of oxidative stress (OS) in human health and disease. Specifically, his research focuses on mechanisms of oxidative lipid damage and the antioxidant roles of high-density lipoproteins (HDL. This research includes pure biomarker method development and validation employing primarily high pressure liquid chromatography (HPLC) and liquid chromatography-mass spectrometry (LC-MS) along with collaborative clinical studies of the role of oxidative stress in cancer, infertility and women’s health, and neurological disease. Current studies on-going in Dr. Browne’s laboratory include investigations of the role of HDL and PON1 in embryo morphology outcomes during in vitro fertilization (IVF), a study of the role of oxysterols in Multiple Sclerosis disease progression and investigations of the role of bioactive lipid mediators in response to air pollution.
Neurology; Neurodegenerative disorders; Pathophysiology; Apoptosis and cell death; Cytoskeleton and cell motility; Molecular and Cellular Biology; Molecular genetics; Neurobiology; Protein Folding; Gene Expression; Transcription and Translation; Signal Transduction; Toxicology and Xenobiotics
My research is aimed at finding the cause and a cure for Parkinson’s disease. Parkinson’s disease (PD) is defined by a characteristic set of locomotor symptoms (rest tremor, rigidity, bradykinesia and postural instability) that are believed to be caused by the selective loss of dopaminergic (DA) neurons in substantia nigra. The persistent difficulties in using animals to model this human disease suggest that human nigral dopaminergic neurons have certain vulnerabilities that are unique to our species. One of our unique features is the large size of the human brain (1350 grams on average) relative to the body. A single nigral dopaminergic neuron in a rat brain (2 grams) has a massive axon arbor with a total length of 45 centimeters. Assuming that all mammalian species share a similar brain wiring plan, we can estimate (using the cube root of brain weight) that a single human nigral dopaminergic neuron may have an axon with gigantic arborization that totals 4 meters. Another unique feature of our species is our strictly bipedal movement, which is affected by Parkinson’s disease, in contrast to the quadrupedal movement of almost all other mammalian species. The much more unstable bipedal movement may require more dopamine, which supports the neural computation necessary for movement. The landmark discovery of human induced pluripotent stem cells (iPSC) made it possible to generate patient-specific human midbrain dopaminergic neurons to study Parkinson’s disease. A key problem for dopaminergic neurons is the duality of dopamine as a signal required for neural computation and a toxin as its oxidation produces free radicals. Our study using iPSC-derived midbrain dopaminergic neurons from PD patients with parkin mutations and normal subjects shows that parkin sustains this necessary duality by maintaining the precision of the signal while suppressing the toxicity. Mutations of parkin cause increased spontaneous release of dopamine and reduced dopamine uptake, thereby disrupting the precision of dopaminergic transmission. On the other hand, transcription of monoamine oxidase is greatly increased when parkin is mutated. This markedly increases dopamine oxidation and oxidative stress. These phenomena have not been seen in parkin knockout mice, suggesting the usefulness of parkin-deficient iPSC-derived midbrain DA neurons as a cellular model for Parkinson’s disease. Currently, we are using iPS cells and induced DA neurons to expand our studies on parkin to idiopathic Parkinson’s disease. We are also utilizing the molecular targets identified in our studies to find small-molecule compounds that can mimic the beneficial functions of parkin. The availability of human midbrain DA neurons should significantly speed up the discovery of a cure for Parkinson’s disease.
Surgery; Surgical Critical Care - Surgery; Surgery - Trauma; Surgery - Laparoscopic; Pathophysiology
I am an acute care surgeon board-certified in both surgery and surgical critical care. The most important part of my job is providing compassionate care to my patients, who are often acutely injured and/or critically ill. I have a deep awareness of, and empathy for my patients’ suffering, and I do my best to alleviate it. My clinical focus is in trauma, critical care and emergency general surgery. I also perform laparoscopic surgery, gastrointestinal surgery (small bowel, colorectal and biliary), complex hernia surgery, as well as endoscopy and wound care. My research is focused on improving care for injured and critically ill patients, including topics in gut-origin bacterial translocation, aspiration and acute respiratory distress syndrome (ARDS), damage control resuscitation and imaging in trauma. I was a co-investigator on NIH-funded grants for evaluation of aspiration biomarkers in trauma and surgery, as well as on an SIS multicenter study on duration of antibiotics for abdominal infection. I encourage medical students and residents to approach me for collaborative research opportunities. The research experience will enable them to develop critical thinking and help shape their practice of medicine. I have mentored numerous surgical residents and medical students in research, which has led to them receiving national research awards. I have a passion for teaching medical students and residents. I find satisfaction in sharing my knowledge and experience with those in the training phase of their careers. In return, their questions help me stay current in my field and ultimately help me render the best care to my patients. I am the course director of the elective internship in trauma. I also give lectures on traumatology to medical students. As a surgeon, role model and educator, I have inspired many medical students to pursue surgery as a career.
Cardiovascular Disease; Internal Medicine; Nephrology; Pathophysiology; Vascular and Interventional Radiology; Cardiac pharmacology
(1) Role of the sympathoadrenal system in hypertension, postural adaptation, and long-term cardiovascular adaptation (2) Control of regional and systemic blood flow during acute stress responses (3) Mechanisms of stress responses and vasoreactivity, both in vivo and in vitro, including metabolic interactions (4) Cardiovascular drug effects (5) Outcomes of drug therapies
Ophthalmology; Retina; Pediatric Ophthalmology; Pathophysiology; Vision science
Dr. Reynolds has various research interests in pediatric ophthalmology, but his main niche is retinopathy of prematurity. ROP is a disease of the developing immature retinal vasculature, modulated by hyperoxia/hypoxia micro environments in the retina, which can lead to neovascularization, scarring, and potential blindness. Dr. Reynolds is a recognized expert in the field and is the author of many peer reviewed articles and several invited review chapters. His NIH funding has been nearly continuous while at U.B. while participating in several multi-center clinical trials in ROP as center P.I. and project director. Dr. Reynolds was the center P.I. at U.B. for the first large treatment trial for ROP, CRYO-ROP. This trial established the first known effective treatment for this high socioeconomic impact disease. As center P.I. he participated in the group collaborative publications as well as co authoring many individually by-lined papers (Ref. 22, 23, 24, 25, 26, 28, 29, 31, 32, 37, 40, 42). His successful and productive work as a center P.I. on this trial led to the funding for the LIGHT-ROP multi-center trial for which he served as project director and lead P.I. This trial definitively answered a long debated hypothesis in ROP i.e. that ambient light was not a causal factor in ROP (Ref. 38, 41, 45, 47). Dr. Reynolds was again selected as a center P.I. for the next large multi-center ROP trial, ET-ROP, which just reported its primary results demonstrating that earlier laser treatment for this disease was effective. Although all multi-center clinical trials are cooperative agreements at the NIH and thus are funded as UO1s rather than RO1s, Dr. Reynolds was an integral participant in all the ROP trials from the mid-eighties to the present, leading one, and actively co-authoring many of the studies?publications as noted in the bibliography. The future of Dr. Reynolds?ROP research will undoubtedly involve more funded multi-center trials. However, a basic science collaboration into the pathophysiology of ROP in an animal model is planned, investigating the renin-angiotension connection.
Retina; Gene therapy; Neurodegenerative disorders; Pathophysiology; Protein Folding; Gene Expression; Signal Transduction
I am a Clinician Scientist working in the field of hereditary retinal and macular degenerations. I direct a regional referral service for these diseases at the Ross Eye Institute. My NIH- and VA-funded laboratory is focused on the development of gene-based therapeutics for hereditary retinal degenerations and common age-related macular degeneration.
Neurodegenerative disorders; Pathophysiology; Cytoskeleton and cell motility; Molecular Basis of Disease; Molecular and Cellular Biology; Neurobiology; Neuropharmacology; Signal Transduction
Synaptic Mechanisms of Mental Health and Disorders Our research goal is to understand the synaptic action of various neuromodulators that are linked to mental health and illness, including dopamine, stress hormones, and disease susceptibility genes. Specifically, we try to understand how these neuromodulators regulate glutamatergic and GABAergic transmission in prefrontal cortex (PFC), which is important for emotional and cognitive control under normal conditions. We also try to understand how the aberrant action of neuromodulators under pathological conditions leads to dysregulation of synaptic transmission in PFC, which is commonly implicated in brain disorders. The major techniques used in our studies include: • whole-cell patch-clamp recordings of synaptic currents, • viral-based in vivo gene transfer, • biochemical and immunocytochemical detection of synaptic proteins, • molecular analysis of genetic and epigenetic alterations, • chemogenetic manipulation of neuronal circuits, • behavioral assays. By integrating the multidisciplinary approaches, we have been investigating the unique and convergent actions of neuromodulators on postsynaptic glutamate and GABAA receptors, and their contributions to the pathogenesis of a variety of mental disorders, including ADHD, autism, schizophrenia, depression, PTSD and Alzheimer's disease.
Cytoskeleton and cell motility; Genomics and proteomics; Ion channel kinetics and structure; Membrane Transport (Ion Transport); Molecular and Cellular Biology; Pathophysiology; Regulation of metabolism
1. Mechanism and regulation of gastric acid secretion: Regulation of gastric acid secretion is the major treatment of many GI diseases including GERD, gastric, duodenal and esophageal ulcers. The spending in treating these conditions is substantial. The gastric parietal cell, lining the lumen of the stomach, is responsible for the secretion of isotonic HCl (0.15M) into stomach. One ATP is consumed for every proton secreted into the stomach lumen and a lot of proton pump (H,K-ATPase, the alpha and beta subunits of this enzyme were discovered in 1967(1) and 1990(2)) is required for this job. To accommodate these many proton pumps, the apical plasma membrane, in the resting state, is expanded in the form of numerous invaginations which express relatively short microvilli, and a large compartment of cytoplasmic membranes, commonly called tubulovesicles, fully loaded with proton pumps. Upon stimulation by hismatine initiated PKA signaling, these tubulovesicles traffic to and fuse with apical membrane, forming densely packed microvilli comparable to those found on the brush border membrane of small intestine. This intracellular trafficking and fusion events bring proton pumps to their post for active acid secretion. In time, these proton pumps are brought back into the cytoplasm (by way of endocytosis) for a reliable mechanism to turn off acid secretion. Although the membrane recycling theory was raised a long time ago(3), there are still many major gaps in the understanding of the mechanism for the regulation of acid secretion, which are the research interests of our laboratory. Techniques employed include isolation and primary culture of gastric parietal cells, measurement of acid secretion, fractionation of different membranes by differential and gradient centrifugation. 2. Using gastric parietal cell model to study general cell biological questions: how membrane trafficking is regulated by small G-proteins, how filamentous actin supports the dynamic change of microvilli on apical membrane. The parietal cell has a remarkably large volume of intracellular membrane trafficking adapted to the elegant mechanism for the regulation of acid secretion. This means that this cell is abundant in those protein machineries required for membrane trafficking and fusion, exocytosis and endocytosis. For instance, no other cell type expresses the amount of syntaxin3 found in parietal cell. Therefore, parietal cell is the top choice for elucidating many of the core questions in cell biology. Techniques used to attack these questions include immunoabsorption, differential ultra-centrifugation, IMAC, 2D-electrophoresis, LC-MSMS, and confocal microscopy. 3. Pathogenesis of Nonalcoholic Steatohepatitis (NASH) - NASH research is funded by the Peter and Tommy Fund. NASH is a disease of the liver that is associated with obesity and adult onset, or type II, diabetes. NASH is not a benign disease. Many people with NASH have a shorter life expectancy than those who no not have NASH. NASH is associated with cirrhosis and is the third most common reason for liver transplantation in adults. No one knows what causes NASH, but it is known that in obese people there is increased fat in the liver. In addition to fat, cells that cause inflammation are found in the liver in patients with NASH. It is thought that these inflammatory cells may cause liver damage that results in fibrosis, cirrhosis and ultimately liver failure. The purpose of this research is to understand the relationship between obesity and the molecular factors that control inflammation so the interaction of the two can be better understood and treatments developed. NASH and alcoholic steatohepatitis share many histological features. Both NASH and alcoholic steatohepatitis patients exhibit macrovesicular and microvesicular fat in hepatocytes. The number and size of Mallory bodies, and the pattern of pericellular fibrosis are also indistinguishable between two disease groups. Previous studies suggested that intestinal bacteria produced more alcohol in obese mice than lean animals. Therefore, we hypothesized and provided the first molecular evidence that alcohol metabolism contributes to the pathogenesis of NASH (Baker et al, 2010). Fatty liver is a prerequisite for the development of NASH. The homeostasis of hepatic lipid depends on the dynamic balance of multiple metabolic pathways. Previous studies focusing on individual pathway or enzyme drew conflicting conclusions on the molecular mechanism for the accumulation of lipid in hepatocytes. With a high through-put technique, we compared all the major pathways in parallel. We are expecting to publish the exciting results in the near future. Oxidative stress is believed to be a major factor mediating the transition from simple steatosis to NASH. The prevention or mitigation of oxidative stress in patients with simple steatosis could prevent NASH. Our current research examines two facets of this problem: 1) what are the molecular mechanisms causing oxidative stress; 2) what are the molecular mechanisms that our body take to fight oxidative stress. Many novel findings have been observed in the lab and we are in the process of confirming these observations. 4. Pathogenesis of Inflammatory Bowel Diseases (IBD): The etiology of IBD is unknown, but a body of evidence from clinical and experimental observation indicates a role for intestinal microflora in the pathogenesis of this disease. An increasing number of both clinical and laboratory-derived observations support the importance of luminal components in driving the inflammatory response in Crohn‘s disease. Members of the Toll-like receptor family are key regulators of both innate and adaptive immune responses. These receptors bind molecular structures that are expressed by microbes but are not expressed by the human host. Activation of these receptors initiates an inflammatory cascade that attempts to clear the offending pathogen and set in motion a specific adaptive immune response. Defects in sensing of pathogens or mediation of the inflammatory cascade may contribute to the pathophysiology of disease and injure the host by activating a deleterious immune response, such as in inflammatory bowel disease. The focus of this research is to identify specific toll-like receptor mutations that may be associated with the development of inflammatory bowel disease.