Research Opportunities

Research Projects: Dr. V. Cardenas
- The role of open lung biopsy in patients with diffuse infiltrates and respiratory failure
- Venovenous extracorporeal gas exchange in the treatment of acute respiratory failure in COPD patients
- Open label trial of vancomycin vs. linezolid in the treatment of MRSA ventilator associated pneumonia
- Randomized trial of activated protein C in patients with lower risk of death from sepsis.
- Efficacy of (R,R) Formeterol in COPD at various doses
- Predictive value of respiratory mechanics in weaning patients from mechanical ventilation

Rheumatology

Endocrinology

Randall J. Urban, M.D.
Research projects

Our group is involved in a variety of clinical and basic research projects in the field of endocrinology. The two primary focuses of the clinical research projects are hypopitutitarism in subjects who sustain a traumatic brain injury (TBI) and the effects of androgens on muscle function in older individuals. We have just received funding for a 3-year project that will identify patients one-year post-TBI who will be screened for pituitary dysfunction. Subjects will be identified as deficient in thyroid, cortisol, and growth hormone and given replacement therapy with specific outcomes measured to assess for clinical improvement. We currently have a clinical research protocol ongoing assessing the effects of nutritional supplementation and androgen therapy on muscle function in older men and women. Techniques in this protocol include learning stable isotope technology, muscle biopsies, measurements of physical function, and Western analysis of muscle protein.

The primary focus of the basic research projects in the group is studying the regulation of steroidogenesis through molecular studies on IGF-I control of P450scc gene expression in porcine granulosa cells. Techniques associated with this project include cell culture, gene transfection to study function, cloning, immunoprecipitation, and protein chemistry to assess protein-protein interactions. A second basic research project involves the use of stem cells from umbilical cord blood to differentiate stem cells into insulin producing beta cells. This project will be associated with the use of proteomics to assess the proteins involved in cell conversion.

Allan R. Brasier, M.D.
Professor of Internal Medicine
Associate Director, HLBI Proteomic Center
MRB 8.138
Phone: X2-2824
arbrasie@utmb.edu

Inflammation plays a critical role in pathobiology of numerous human disease states including inflammation, hypertension, wound repair, and malignancy. In any given tissue, inflammation can be induced by the effect of infectious agents or extracellular hormones that activate intracellular signals. Cells respond to these stimuli through signal transducing molecules which alter genetic responses to restore homeostasis. Work in my laboratory is broken into two separate projects: 1. The mechanisms for the hepatic acute-phase response, a genetic response to inflammatory hormones stimulating the liver, and 2. The mechanisms for how the respiratory epithelium induces airway inflammation in response to viral infection. These research activities focus on cutting edge molecular biology on cell and animal models.

The hepatic acute phase response is a homeostatic response to systemic infection or inflammation which induces the liver to secrete proteins important in wound repair and blood pressure regulation. Released at the local site of infection by activated macrophages, circulating inflammatory cytokines, such as tumor necrosis factor-a (TNFa), activate expression of genetic networks in the liver. We have shown that, the acute phase reaction is mediated, in part, through activating nuclear translocation of the cytoplasmic transcription factor, nuclear factor-kB (NF-kB). NF-kB is sequestered in the cytoplasm by association with inhibitory proteins termed IkBs. In TNFa-stimulated cells, IkB is rapidly proteolyzed, releasing NF-kB to enter the nucleus and stimulate transcription of acute-phase reactants. Our lab was the first to define a pathway for inducible degradation of the IkB protein by cytosolic calcium-activated neutral endoproteases (calpains). We have further shown an essential role of the IkB proteins, IkBa and BCL-3, in terminating NF-kB by capturing nuclear NF-kB and return it into the cytoplasm. Additionally, we demonstrated that angiotensin II, a potent vasopressor peptide, also activates inflammatory cytokine expression through NF-kB in the liver and vessel wall. Currently, our lab is investigating the role of the specific IkB kinases IKKg and the NF-kB inducing kinase (NIK) in mediating NF-kB activation. We have established a mouse model for development of accelerated atherosclerosis by angiotensin II and we are using this to investigate how angiotensin II produces atherosclerosis.

Viral infections are linked to exacerbations of airway hyperreactivity (asthma). Also in my laboratory we investigate the mechanism for the pulmonary cytokine cascade activated by Respiratory syncytial virus (RSV) infection. RSV is a ubiquitous pathogen that infects virtually 100% of the US population before the age of three and is responsible for 100,000 hospitalizations annually. RSV produces a pronounced inflammatory response in airways of children with active infection; this is a consequence of inflammatory mediators (cytokines) produced by airway epithelial cells. These cytokines recruit and activate various populations of immune cells into the respiratory mucosa. We have demonstrated that RSV-infected alveolar epithelial cells inducibly transcribe and secrete families of chemokines including IL-8, RANTES, Exodus-1, TARC and Fractalkine. We are presently investigating the role of NF-kB in mediating inflammatory response using “gene chip” microarrays and proteomic technologies. This work involves identifying viral induced kinase complexes by affinity purification and mass spectrometry. These studies are part of the HLBI funded Proteomic Center at UTMB (http://www.bioinfo.utmb.edu/proteomics/NHLBI/).

Work in my lab is supported by grants from the National Heart Lung and Blood Institute, and National Institute of Allergic and Infectious Diseases.

Peer Reviewed Publications (last 2 years):

1. Jamaluddin, M., Wang, S., Garofalo, R.P., Elliott, T., Casola, A., Baron, S., Brasier, A.R.IFN-b mediates coordinate expression of antigen processing genes in RSV-infected pulmonary epithelial cells. American Journal Physiology, Lung Cell Molecular Physiology, 280: L248-L257, 2001.

2. Sherman CT and Brasier AR. Role of STAT 1 and STAT3 in inducible expression of human angiotensinogen gene by IL-6. Molecular Endocrinology, 15: 441-447, 2001.

3. Casola, A., Garofalo, R.P., Haeberle, H ., Elliott, T., Jamaluddin, M., Brasier, A.R. Multiple inducible cis elements control RANTES transcription in alveolar epithelial cells infected with RSV. Journal of Virology, 75: 6428-6439, 2001.

4. Casola, A., Burger, N., Liu, T., Jamaluddin, M., Brasier, A.R., Garofalo, R.P. Oxidant tone regulates RANTES gene expression in airway epithelial cells infected with RSV. Journal of Biological Chemistry, 276: 19715-19722, 2001.

5. Lu, Y., Jamieson, L., Brasier, A.R., and Fields, A.P. NF-kB/Rel A Transactivation Is Required for Atypical Protein Kinase Ci-Mediated Cell Survival. Oncogene, 20: 4777-4792, 2001.

6. A. R. Brasier, Lu, M., Hai, T., Lu, Y., and Boldogh, I. Inducible Expression Of Cytoplasmic BCL-3 In An Autoregulatory Loop Terminating NF-kB Action. Journal of Biological Chemistry, 276: 32080-32093, 2001.

7. Zhang, Y., Luxon, B. A., Casola, A., Garofalo, R.P., Jamaluddin, M., and Brasier A.R. Expression Of RSV-Induced Chemokine Gene Networks In Lower Airway Epithelial Cells Revealed By cDNA Microarrays. Journal of Virology, 75: 9044-9058, 2001.

8. Botion, L.M., Brasier, A.R., Tian, B., Udupi, V. and Green A. Inhibition of Proteasome Activity Blocks the Ability of Tumor Necrosis Factor-alpha to Down-Regulate Gi-proteins and Stimulate Lipolysis. Endocrinology, 142: 5069-5075, 2001.

9. Brasier, A.R.Retriever And CompareTable, Two Informatics Tools For Data Analysis Of High Density Oligonucleotide Arrays., BioTechniques, 32: 100-109, 2002.

10. Ray, S., Sherman, C.T., Lu, M. and Brasier, A.R. Angiotensinogen gene expression is dependent on Signal Transducer and Activator of Transcription 3-mediated p300/CBP coactivator recruitment and Histone Acetyltransferase activity. Molecular Endocrinology, 16: 824-836, 2002.

11. Tian, B., Zhang, Y., Luxon, B.A., Garofalo, R.P., Casola, A., Sinha, M., and Brasier, A.R. ^† Identification Of NF-kB Dependent Gene Networks In Respiratory Syncytial Virus-Infected Cells. Journal of Virology, 2002; 76:6800-6814.

12. Pazdrak, K., Garofalo, R.P., Olszewska-Pazdrak, B., Liu, T., Brasier, A.R. and Casola, A. ERK activation is involved in post-transcriptional regulation of RSV-induced RANTES gene expression. American Journal of Physiology, Lung Cell and Molecular Biology, 2002, 283: L364-L372.

13. Casola, A., Garofalo, R.P., Crawford, S., Estes, M.K., Mercurio, F.., Crowe, S.E., Brasier, A.R. Interleukin-8 gene regulation in intestinal epithelial cells infected with rotavirus: role of viral-induced IkB kinase activation. Virology, 2002, 298:8-19.

14. Li, J., Kartha, S., Iasvovskaia, S., Tan, A., Bhat, R.K., Manaligod, J.M., Page, K., Brasier, A.R., and Hershenson, M.B.. Regulation of human airway epithelial cell interleukin-8 expression by mitogen-activated protein kinases: Identification of NF-kB dependent and independent pathways. American Journal of Physiology, Lung Cell and Molecular Physiology, 2002, 283: L690-699.

15. Casola, A., Henderson, A., Liu, T., Garofalo, R.P. and Brasier A.R. Regulation of RANTES promoter activation in alveolar epithelial cells after cytokine stimulation. American Journal of Physiology, Lung Cell and Molecular Physiology, 2002, 283: L1280-90.

16. Haeberle, H., Takizawa, R., Casola, A., Brasier, A.R., Hans-Juergen D., van Rooijen, R., Gatalica, Z., Garofalo, R.P. Respiratory syncytial virus-induced activation of NF-kB in the lung involves alveolar macrophages and Toll-like receptor 4-dependent pathways. J Infect Dis 2002; 186:1199-1206.

17. Zhang,, Y., Jamaluddin, M., Tian, B., Wang, S., Casola A. Garofalo, R., and Brasier, AR. Ribavirin Treatment Upregulates Anti-Viral Gene Expression Via The IFN-Stimulated Response Element In RSV-Infected Epithelial Cells. Journal of Virology, 2003; 78: 5933-5947.

Larry Denner, Ph.D. and Ronald Tilton, Ph.D.
Research Projects

Our group is interested in the role of inflammation in diabetes using experimental approaches studying basic signaling mechanisms in cell culture models, animal models of diabetes, and tissue from human diabetic patients. Specific project areas include:

TNF- and glucose-induced regulation of the inflammatory axis in the Thp1 human monocytic cell line and in isolated glomeruli from control and diabetic rats
Inflammation in the pathogenesis of vascular complications in type I (streptozotocin-induced) diabetes in rats and type II diabetes in rats (Zucker) and mice (db/db transgenics)
Inflammatory signaling in human normal and diabetic patient renal cortex, isolated glomeruli, leukocytes, and muscle biopsies

In each of these models, we employ similar technical strategies to understand the spatial and temporal regulation of the composition of multiprotein signaling complexes and the role of phosphorylation in mediating signaling through reactive oxygen species and NF-kB. These include western blotting, immunoprecipitation-western blotting, and 2D gel-based proteomics. We have a pending Texas ATP grant entitled "Development of High sensitivity Technologies to Study the Phosphoproteome", which reflects our intense commitment to analyze, identify, and quantify the role of phosphorylation in regulating these pathways. Finally, the ultimate, long term focus of all these discovery efforts is the identification of targets for therapeutic discovery and development to impact on the quality of life for diabetic patients.

Gastroenterology

Maria-Adelaide Micci, Ph.D.
Assistant Professor

Dr Micci joined the Division of Gastroenterology in the Department of Internal Medicine at UTMB in 1998. Her current research focuses on studying gastrointestinal motility disorders both at the cellular and molecular level. In particular, her research focuses on the biology of neural stem cells and their application for transplantation in the GI tract. Dr. Micci is currently Co-Investigator in a NIH-R01 looking at the use of neural stem cells for the treatment of achalasia and other neurodegenerative gastrointestinal disorders. An outline of the proposal is summarized below.

Neural stem cells (NSC) are primordial uncommitted cells postulated to give rise to the array of specialized cells in the central nervous system. Following implantation in animals, these cells appear to respond to local cues and begin to specialize appropriately. They have been shown to develop into cells of most neuronal and glial (support cells) lineage and have the potential for treating a wide variety of neurodegenerative conditions such as Parkinson’s disease. Transplantation of these cells could also be of benefit therefore in degenerative conditions of the enteric nervous system such as achalasia, a disorder of swallowing caused by a local loss of nerve cells.

Dr. Micci began working in this area in 1999 and preliminary experiments, funded by the Texas Board of Higher Education, have demonstrated that NSC isolated from rat forebrain can, not only produce key neurotransmitters such as NO but also be successfully transplanted into the stomach of mice where they differentiate into neuron and survive up to 8 weeks. Moreover, these cells are able to form functional neuromuscular connections and may be able to modulate gastric emptying. These studies therefore support the hypothesis that transplantation of CNS-NSC is a promising cellular replacement strategy for enteric neurons.

Having established the feasibility of neuronal transplantation into the gut, Dr. Micci is now engaged in a series of experiments designed to determine the optimal conditions required for successful engraftment and functional benefit.

1: To determine the post-implantation fate (survival and differentiation) of transplanted CNS-NSC, and to assess the benefit, if any, of immunosuppressive therapy in this setting.

2: To determine the role of the GDNF-RET system, if any, in determining the post-implantation fate of transplanted CNS-NSC.

3: To determine the physiological/functional effects of transplanted CNS-NSC on the gastrointestinal motility of mice with targeted disruption of the neuronal nitric oxide synthase gene (nNOS -/-).

Dr. Micci is also working on a project looking at the effect of local injection of Botulinum toxin A (BoNT A) into the gastrointestinal wall of experimental rats. BoNT A is increasingly being used therapeutically to reduce smooth muscle tone in a variety of gastrointestinal disorders. However, the neuromuscular effects of this drug in the unique environment of the enteric nervous system have not been well studied. The aim of the study is to determine whether the effects of BoTox A on GI contractility are similar to those on skeletal muscle in that they are predominantly cholinergic, and gradually wear off.

ARTICLES IN PEER-REVIEWED JOURNALS:

Alema GS. Maccari S. Micci MA. Patacchioli FR. Hippocampal serotonin in the regulation of the hypothalamo-pituitary-adrenocortical axis (HPAA) stress response. Pharmacological Research Communications. 20(5):429-30, 1988.

Choate, J.V.A.; Kruger, T.E.; Micci, M.A.; Blankenship, J.E. Isolation of an egg-laying hormone-binding protein from the gonad of Aplysia californica and its localization in oocytes. J. Comp. Physiol. A, 173:475-483; 1993.

Micci, M.A., Christensen, B.N. Distribution of inositol trisphosphate receptor in the catfish retina. Brain Res. 720:139-147; 1996.

Micci, M.A., Christensen, B.N. Sodium/Calcium exchange in catfish retinal horizontal cells and its role in the regulation of intracellular calcium store function. Am. J. Physiol.: Cell Physiol., 274: C1625-C1633; 1998.

Yallampalli S., Micci M.A. and Taglialatela G. Ascorbic acid prevents beta-amyloid-induced intracellular calcium increase and cell death in PC12 cells. Neurosci. Letters 251 (2): 105-108, 1998.

Toma, H., Winston, J., Micci, M.A., Shenoy, M. and Pasricha, P.J. Nerve Growth Factor expression is up-regulated in experimental pancreatitis. Gastroenterology, 119 (5): 1373-1381, 2000.

Micci M.A., Learish R.D., Li H., Abraham B. and Pasricha P.J. Neural stem cells express RET, produce nitric oxide and can survive transplantation in the gastrointestinal tract. Gastroenterology 121:757-766, 2001.

Hoogerwerf W.A., Zou L., Shenoy M., Micci M.A., Hellmich H., Xiao S.Y., Winston J.H. and Pasricha P.J. The proteinase-activated receptor 2 is involved in nociception. J. Neurosci. 21: 9036-9042, 2001.

Toma H. Winston JH. Micci MA. Li H. Hellmich HL. Pasricha PJ. Characterization of the neurotrophic response to acute pancreatitis. Pancreas. 25(1):31-8, 2002.

Hoogerwerf WA, Hellmich HL, Micci MA, Zou L, Winston JH, Pasricha PJ Molecular cloning of the rat proteinase-activated receptor 4 (PAR4) BMC Molecular Biology 3:2, 2002

Winston JH, Toma H, Shengoy M, He ZH, Zou L, Xiao SY, Micci MA, Pasricha PJ Acute Pancreatitis Results in Referred Mechanical Hypersensitivity and Neuropeptide Up-Regulation That Can Be Suppressed by the Protein Kinase Inhibitor K252a. The Journal of Pain 4(6): 329, 2003

Infectious Diseases

Joan E. Nichols, Ph.D.

The interest of my laboratory is the etiology and pathogenesis of viral infections caused by RNA viruses. Our research mixes aspects of both virology and immunology in order to assess the impact of virus and/or host factors on the development of clinical disease, generation of the immune response and development of immune memory. To delineate the role of influenza determinants of virulence, we are currently evaluating viral components that influence virulence using natural reassortants of attenuated and wild type viruses as well as manipulation of the virus genome using reverse genetics. We are interested in the role of pro-inflammatory cytokines, expression of cell surface mediators and the processes of cellular signaling on the development of clinical disease. Currently I am evaluating the role of influenza neuraminidase production/activity on the induction of apoptosis of peripheral blood lymphocytes and the relationship between lymphocyte apoptosis and the development of clinical disease. We are also interested in age-associated alterations in innate immunity which decrease antigen presenting cell function (the innate immune response) and influence lymphocyte responses (adaptive immunity) to viral pathogens such as influenza and respiratory syncytial virus.

William A. O’Brien, M.D., M.S.

Our AIDS research laboratory is engaged in a wide variety of research activities, principally related to translational research, i.e., addressing clinically important issues in the laboratory. Our focus is HIV drug resistance and HIV entry. Our basic research program is involved both in understanding mechanisms of HIV entry, as well as using structural biology to develop novel inhibitors of HIV entry. We are also involved in clinical diagnostic virology, and perform genotypic HIV drug resistance testing using several different technologies available in our laboratory. There are many opportunities for house staff to participate, including chart review to obtain information for clinical samples we may analyze in the laboratory, assessment of the impact of drug resistance on response to future therapies, again largely involving chart review, processing of clinical samples for recovery of RNA and performance of diagnostic testing, and straightforward molecular biology experiments in which HIV specific DNA or RNA are cloned and manipulated in plastid constructs in the laboratory. Procedures for bench work are well outlined in protocol manuals, and there are three postdoctoral researchers, two Ph.D. graduate students and two technicians who are available to help with completion of projects. House staff that are interested in experience in cutting-edge HIV research can contact me.

Norbert J. Roberts, Jr., M.D.

My research group studies viral pathogenesis with particular interest in influenza virus and respiratory syncytial virus (RSV) infections. Our particular interest is in the role of active infection of human mononuclear leukocytes by viruses in the course of a developing antiviral response. Our studies use a combination of virologic and immunologic approaches and methods, and commonly are oriented toward analysis of virus-leukocyte interactions at the single cell level using flow cytometric assays. The viral infections of the leukocytes are examined at both the molecular and cellular level, and regulation of responses by both monocytes-macrophages and lymphocytes is assessed. Many of the studies are conducted in collaboration with Drs. Joan E. Nichols and Robert A. Davey.

Current studies address:

The mechanisms whereby RSV causes recurrent clinical infection in individuals who have evidence of immunity to the virus. The aims are to identify the viral component(s) that attenuate and/or delay the development of an anamnestic immune response, and immediate-early gene expression by the virus-exposed leukocytes that determines the outcome of the challenge.
The impact of HLA-associated determinants on influenza virus infection of leukocytes. The aims are to characterize the intrinsic resistance of lymphocytes with certain HLA haplotypes to infection by influenza virus, and to determine the extent to which this might influence population survival during pandemic or highly pathogenic influenza virus infection.
The regulation of immune responses in the lung, such that constant inflammation in response to inhaled material is avoided or suppressed but an immune response to a pathogen such as influenza virus is initiated and recovery is assured.

Nephrology

“Signal Transduction and Regulation of Renal Transport”.
David Good, Ph.D.

Our laboratory is interested in physiological factors and cellular mechanisms involved in the regulation of electrolyte transport in the kidney. Emphasis is on signal transduction pathways involved in regulation of Na/H exchange activity and acid secretion in the thick ascending limb by hormones and growth factors. Projects include study of the biochemical pathways mediating nongenomic regulation by aldosterone and analysis of the potentially detrimental effects on renal transport of the immunosuppressive drug rapamycin. Experimental approaches include measurement of intracellular ion activities in microdissected renal tubules using fluorescent dyes, biochemical analyses of signaling proteins, and confocal microscopic analysis of cytoskeletal structure. Meaningful participation in projects would require a minimum commitment of three to six months.

James (Jim) Rice, MD
Associate Professor, Nephrology
4.200 JSA, Route 0562
301 University Blvd.
University of Texas Medical Branch
Galveston, Texas 77555
Off: (409)-772-8605
Fax: (409)-772-5451

TITLE: Mucosal Immune Response in the Kidney to Ascending Infections and Ischemia

GOALS: The overall objective of the Rice Immuno-Nephrology Lab is to look at the mucosal immune response of the kidney to infection and ischemia. The main foci of our research are two-fold: 1) a mouse urinary tract infection (=PYELO NEPHRITIS PROJECT) and 2) studies into the role of ischemia on the the renal immune response (=RENAL ISCHEMIA PROJECT).

DESCRIPTION: At present, our main focus in the lab is the PYELO PROJECT. We are looking at the interaction of bacteria and renal epithelial cells in the mucosal immune response of the kidney. Specifically, we are investigation the role(s) of bacteria, epithelial cell chemokines, and LPS in ascending urinary tract infection. We have found increased chemokines in the kidney during ascending bacterial infection (pyelonephritis). Our focus is to determine the effect of P antigen (bacterial adhesin) on renal tubule epithelial cell chemokines (mRNA, protein).

A second aspect of the PYELO Project focuses on the role of IgA in the mucosal immunoglobulin response to infection. Specifically, we have focused on the polymeric immunoglobulin receptor, or pIgR, which is responsible for the transport of IgA through the renal epithelia into the urinary space. IgA combined with secretory component (fragment of pIgR) functions to prevent adhesion of pyelonephritic strains of bacteria to the renal epithelia. Our goal of this project is to determine if pIgR expression changes in the kidney during acute pyelonephritis. Our preliminary data suggests there may be a decrease in pIgR levels in HeJ (LPS-insensitive) mice. We are completing evaluation of pIgR mRNA in C3H/HeN mice.

LEARNING OPPORTUNITIES: This lab offers the opportunity to work in the emerging fields of mucosal immunity in the kidney. Although a basic lab, the project is quite clinically oriented and applicable. Lab personel are involed in animal surgery and care, microbiologic techniques, molecular biology (including RNA, DNA isolation and analysis), immunologic techniques (ELISA, immunohistolchemisty) and protein assays. The lab is composed of Dr. Tao Peng (Post-Doctoral) and Dr. James Rice (Assoc. Prof., Internal Medicine) and our collaborators Dr. Bogdan Nowicki (Professor-Ob-Gyn, Microlbiology) and Dr. Randall Goldblum (Professor, Pediatrics, Director of Child Health Research Center).

TIME FOR ACCEPTING RESIDENTS: The lab is funded and active throughout the academic year. Ongoing laboratory experiments are performed daily by Dr. Tao Peng, a post-doctal fellow in Dr. Rice's lab. Coordination with Dr. Jim Rice's schedule to allow for maximum interaction during the research training session is strongly encouraged. Depending on the time commitment, it is expected that the intern or resident will complete a project and be prepared to submit their work to a scientific session. Future projects will focus on the stress activated protein kinase signalling pathways that occur post infection in the kidney and the interactions of pyelonephritis and ischemia-reperfusion in chronic renal allograft dysfunction.

We look forward to working with dedicated interns and residents that are interested in working in the areas of immunology, microbiology and nephrology and are able to commit to 2-3 month periods in the lab.

Regulation of Renal Transport by Neurotrophins
Bruns A. Watts III, Ph.D.

Summary:
Research in my laboratory examines the role of neurotrophins in regulation of renal epithelial transport. Neurotrophins are produced in a wide variety of neural and non-neural tissues including the kidney; however, the role of neurotrophins in renal function is largely unknown. Two neurotrophins, nerve growth factor and neurotrophin-3, regulate renal function by inhibiting bicarbonate absorption in the medullary thick ascending limb segment of the nephron, a process that is mediated by the apical membrane sodium-hydrogen exchanger. This transport protein also is responsible for the majority of sodium reabsorption by the kidney. Thus, in addition to their role in regulation of whole body acid-base balance, neurotrophins may play an important role in regulating sodium retention by the kidney. The goals of this project are to examine the mechanisms by which neurotrophins regulate renal epithelial transport and to assess chronic regulation of neurotrophins in the kidney in response to clinically-relevant physiologic conditions.

The role of neurotrophins in regulation of renal epithelial transport will be examined by studying the cellular mechanisms involved in acute regulation of transport by neurotrophins and assessing chronic regulation of renal neurotrophins and their receptors. Renal tissue from rats will be studied in vitro to examine the following questions: 1) Does neurotrophin-3 inhibit bicarbonate absorption through direct inhibition of apical membrane sodium-hydrogen exchange activity?, 2) Which receptors and intracellular signaling mechanisms are involved in the inhibition of bicarbonate absorption by neurotrophin-3?, and 3) Do chronic changes in water balance alter renal expression of neurotrophins or the functional response to neurotrophins? Ion transport, protein expression, kinase activities, and protein tyrosine phosphorylation will be studied coordinately to provide a detailed understanding of the mechanisms involved in regulation of renal epithelial transport by neurotrophins.

These studies will advance our understanding of the signaling mechanisms involved in regulation of sodium-hydrogen exchange and epithelial transport by neurotrophins and provide important new information on the mechanisms involved in long-term regulation of renal neurotrophin responses. Understanding the role of neurotrophins in regulation of renal transport is critical for defining their potential contributions to the normal renal function (e.g., maintaining sodium and acid-base balance) and to sodium retention in hypertension.

Techniques:
Immunoprecipitation, Immunoblotting, Immunohistochemistry, Protein kinase assay, Animal handling, Tissue dissection
Time
Commitment of 2-3 months in the laboratory

Pulmonary & Critical Care

Research Projects
Dr. V. Cardenas
Pulmonary and Critical Care Medicine

The role of open lung biopsy in patients with diffuse infiltrates and respiratory failure
1. Description: investigator initiated retrospective chart review
2. Houseofficer role: chart review and data entry in database, obtain pathology slide images, assist in preparation of manuscript.
3. Objectives: to define the utility of open lung biopsy in critically ill medical patient with respiratory failure.
4. Abstract submission to the American Thoracic Society International Conference is expected.
Venovenous extracorporeal gas exchange in the treatment of acute respiratory failure in COPD patients
1. Description: investigator initiated Phase I/II clinical trial
2. Objective: to determine the safety and efficacy of VVCO2R in intubated patients with COPD or patients who have foregone the option of mechanical ventilation
3. Houseofficer role: To assist with obtaining data, providing care at the bedside in conjunction with the investigators. May require night shift duties.
4. Abstract submission to the American Thoracic Society International Conference is expected.
Open label trial of vancomycin vs. linezolid in the treatment of MRSA ventilator associated pneumonia
1. Industry sponsored clinical trial, open label, Phase IV
2. Objective: to correlate microbiological cure via bronchoscopy with clinical outcome
3. Houseofficer role:Assist with screening patients, obtaining data, assisting with bronchoscopies.
Randomized trial of activated protein C in patients with lower risk of death from sepsis.
1. Industry sponsored trial, randomized, double blind, placebo controlled, Phase IV
2. Objective: Evaluate efficacy of APC
3. Houseofficer role: Assist with screening patients, obtaining data.
Efficacy of (R,R) Formeterol in COPD at various doses
1. Industry sponsored trial, Phase I/II trial
2. Objective: safety/efficacy trial of bronchodilator in COPD, including pharmacokinetic evaluation
3. Houseofficer role: obtain history and physicals, follow patients in outpatient setting, assist with obtaining and interpreting data including spirometry.
Predictive value of respiratory mechanics in weaning patients from mechanical ventilation
1. Investigator initiated prospective controlled trial
2. Objective: compare two methods of determining frequency to tidal volume ratios in mechanically ventilated patients
3. Houseofficer role: participate in daily screening of patients, perform f/VT measurements, record data.

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