Subspecialty: Nutrition
Department: Surgery
Name (l,f): Albina, Jorge
Faculty Research Website: http://research.brown.edu/myresearch/Jorge_Albina
Location: RI Hospital
Telephone: 444-4296
General Research Area: Wound metabolism
Type of projects available: Title(s): "Bioactivity and immunoprecipitation of murine tumor necrosis factor alpha"; "TNF production in murine macrophages"; "Cloaked oxidant production by wound macrophages"; "Gelatinase production in resting and activated rat macrophages"; "Metabolic changes in macrophages during inflammation"
Course Credit: Yes

Faculty Research Area: JORGE E. ALBINA
Regulation of Cell Function in Inflammation and Tissue Repair

M.D., Universidad Nacional de La Plata, Argentina, 1972. Professor of Surgery. Director, Surgical Research and Director, Nutritional Support Service, Rhode Island Hospital. 444-4296.

Research Summary: Successful wound healing requires the coordinated activities of multiple cell types that constitute the inflammatory and reparative response to tissue injury. The identification of growth factors, cytokines, matrix components and other products present in the wound promises clinical applications that will allow active therapeutic intervention. Development of these applications will require a better understanding of the biology of inflammatory cells, most specifically as it relates to modulation by the wound environment. The laboratory has recently focused its attention on the early events that follow tissue injury. In this regard, the temporal kinetics and cellular basis for the expression of nitric oxide synthase in the wound were characterized, along with the effects of NO production by wound cells on inflammatory cell function. Moreover, recent results challenge current paradigm regarding the resolution of acute inflammation by demonstrating that wound macrophages actively induce apoptosis in wound neutrophils using for this purpose a constitutive effects system comprising beta-3 integrins and membran-bound tumor necrosis factor alpha.

Publications: Reichner, J.S. Meszaros, A.J., Louis, C.A., Henry, W.L., Sr., Mastofrancesco, B., Martin, B.-A and Albina, J.E. Molecular and metabolic evidence for the restricted expression of inducible nitric oxide synthase in healing wounds. American Journal of Pathology 154: 1097-1104, 1999.
Nessel, C.C., Henry, W.L., Jr., Mastrofrancesco, B., Reichner, J.S., and Albina, J.E. Vestigial respiratory burst activity in wound-derived macrophages. Am. J. Physiol. 276:R (in press), 1999.
Meszaros, A.J. , Reichner, J.S., and Albina, J.E. Macrophage phagocytosis of wound neutrophils. Journal of Leukocyte Biology 65:35-42, 1999.
Meszaros, A.J., J.S. Reichner, and J.E. Albina. 2000. macrophage-induced neutrophil apoptosis. J. Immunol. In Press.

Volunteer (academic year): Yes
Index: Inflammation, Wound Healing, Amino Acids, Macrophage, Fibroblast



Subspecialty: Immunology/cell biology
Department: Surgery
Name: Ayala, Alfred
Faculty Research Website: http://research.brown.edu/myresearch/Alfred_Ayala
Location: RI Hosp
Telephone: 444-5158
General Research Area: Immune dysfunction associated with sepsis and shock/trauma
Type of projects available: 1) Assessment of the effects of kupffer cell depletion on the systemic inflammatory cytokine response and host immunity during sepsis; 2) Determination whether sepsis includes apoptosis in macrophage and neutrophils and what are the mediators of this process; 3) Comparison of the effects of low-dose endotoxin infusion to sepsis on the transcription of the inflammatory cytokine genes in mouse macrophage; 4) To determine whether or not evidence of programmed cell death is present in hepatocytes isolated from the liver of septic mice; 5) Examination of whether or not B-cells isolated from Peyer's patches of septic mice exhibit evidence of altered IgA secretion
Course Credit: Yes
Description if different from above: Relevant course work in general biology, chemistry and cell physiology required. Use of mouse model system and/or tissues. Background courses in immunology/biochemistry/molecular biology preferred.

Faculty Research Summary: ALFRED AYALA, Ph.D.

Associate Professor. Ph.D., Cleveland State University, 1986. Rhode Island Hospital Middle House 227
444-5158. AAYALA@lifespan.org

Research Summary: Work in our laboratory is centered on the effects of shock/trauma/sepsis on host cell-mediated immunity. Particular emphasis has been directed toward defining the role of soluble (cytokine, eicosanoids, reactive O2/N2, hormones, microbial toxins, etc.) as well as cellular mediators which may be involved in suppressing host immunity (T/B-cell responsiveness as well as macrophage and granulocyte responses) following trauma and/or during sepsis. With respect to these mediators we have found that the septic or traumatized host produces a number of natural agenst (TGF-beta, IL-4, IL-10, PGE2, NO, testosterone, glucocorticoids as well as catecholaminies) in excess which are immunosuppressive. Interestingly, evidence of altered immune cell apoptosis also is present in these patients/animals examined during sepsis and/or following shock. Inasmuch, we are actively examining the role of these mediators in the induction of immunosuppression and whether of notthis is mediated through aberrant control of immune cell apoptosis. We also have ongoing interests in the role of gender and age with respect to host responsiveness to septic challenge and/or traumatic shock. To address these questions we have applied a wide range of cellular/immunological/biochemical and molecular methods using relevant physiological murine models. It is our hope that by understanding the cellular/moledcular mechanisms which underpin the induction of host immune dysfunction we will be better able to not only assess patient's immune/clinical status, but also to intervene pharmacologically in a way that improves the patient's survival following shock/trauma and/or sepsis.

Publications: Ayala, A., Tu, Y., Flye, M.W., Chaudry, I.H. 1996.Depressed splenic function after hemorrhage results from
gastrointestinal tract stimulation of hepatic-mediator release. Correction with portacaval shunt. Arch. Surg. 131:1209-1215.
Ayala, A., Xu, Y.X., Ayala, C.A., Sonefeld, D.E., Karr, S.M., Evans, T.A., Chaudry, I.H. 1998. Increased mucosal B-lymphocyte apoptosis during polymicrobial sepsis is a Fas ligand but not an endotoxin mediated process. Blood 91:1362-1372.
Song, G.Y., Chung, C.S., Chaudry, I.H., Ayala, A. 1999. Splenic immune suppression in sepsis: a role for IL-10 induced changes in p38 MAPK signaling. J. Surg. Res. 83:36-43.
Song, G.Y., Chung, C.S., Chaudry, I.H., Ayala, A. 1999. What is IL-10's Role in Polymicrobial Sepsis: Anti-inflammatory Agent or Immune Suppressant? Surgery 126:378-383.
Ayala, A., Chung, C.S., Xu, X.Y., Evans, T.A., Redmond, K.M., Chaudry, I.H. 1999. Increased inducible apoptosis in CD4+ T-cells seen during polymicrobial sepsis is mediated by Fas ligand and not endotoxin. Immunology 97:45-55.

Volunteer (academic year): Yes
Summer: Yes
Index: Immunology, apoptosis, mediators, sepsis, infection, shock



Subspecialty: Neurophysiology
Department: Surgery
Name: Bereiter, David
Faculty Research Website: http://research.brown.edu/myresearch/David_Bereiter
Location: RI Hosp.
Telephone: 444-4277
General Research Area: Neuroendocrine physiology
Type of projects available: Projects explore the hypothesis that different neuronal populations within the Vsp mediate different aspects of responses to orofacial pain
Course Credit: X

Faculty Research Summary: DAVID BEREITER, PH.D.

University of Illinois, 1976. Professor of Neuroscience (Research). Dept. of Surgery Rhode Island Hospital. 444-4277

Research Summary: This research focuses on the neural mechanisms that underlie orofacial pain and the accompanying autonomic distrubances. The trigeminal system is well-suited to study the various aspects of pain transmission since the trigeminal nerve innervates several specialized structures that are associated with pain sensation in humans such as the teeth, cornea and temporomandibular joint. The trigeminal nerve fibers that supply these structures project to the CNS and synapse initially within the spinal trigeminal nucleus (Vsp). Thus, central neurons within the Vsp must assume a critical role in the relationship between orofacial pain signaling and the various responses to these signals. The research projects explore the hypothesis that different neuronal populations within the Vsp mediate different aspects of the responses to orofacial pain. Electrophysiology, immunocytochemistry, and microdialysis methods are used to examine the response properties, neurochemical input, and projection targets of Vsp neurons that respons to high intensity stimulation of orofacial structures. Other factors such as cardiovascular and endocrine status as well as possible sex differences in orofacial pain processing are of interest.

Publications: Bereiter, D.A. and A.P. Benetti. Excitatory amino acid release within spinal trigeminal nucleus after mustard oil into the temporomandibular joint region in the rat. Pain 67:451-459, 1996.
Meng, I.D., J.W. Hu, A.P. Benetti and D.A. Bereiter. Encoding of corneal input in two distinct regions of the spinal trigeminal nucleus in the rat: cutaneous receptive field properties, responses to thermal and chemical stimulation, modulation by diffuse noxious inhibitory controls, and projections to the parabrachial area. J. Neurophysiol. 77:43-56, 1997.
Bereiter, D.A. Morphine and somatostatin analogue reduce c-fos expression in trigeminal subnucleus caudalis produced by corneal stimulation in the rat. Neuroscience 77:863-874, 1997.
Meng, I.D., Hu, J.W. and Bereiter, D.A. (1998) Differential effects of morphine on corneal-responsive neurons in rostral versus caudal regions of spinal trigeminal nucleus in the rat. J. Neurophys. 79: 2593-2602.
Index: Orofacial Pain


Department: Surgery
Faculty Research Website: http://research.brown.edu/myresearch/Walter_Biffl
Name (l, f): Biffl, Walter
Location: RIH
Telephone:
General Research Area: Inflammatory and immune response to trauma and transfusion, and the role of the neural patheways in mediating this response.
Types of Projects Available: (1) The role of matrix metalloprotornases in transfusion-related acute lung injury; (2) Signaling pathways that modulate neutrophil cytotoxicity following transfusion; and (3) The role of neural pathways in mediating acute lung injury following ischemia/reperfusion insult.
Course Credit: Yes
Volunteer (academic year): Yes
Summer: Yes
Research Summary: I have a longstanding interest in the role of neutrophil in post injury multiple organ failure. Blood transfusion is a powerful independent risk factor for acute lung injury; stored blood primes neutrophils for enhanced cytotoxicity. I am exploring the signaling pathways that mediate this effect. I have recently found that matrix metalloproteinases (implicated in the pathogenesis of acute lung injury) accumulate over time in stored blood. The mechanism and inhibition of this are the focus of current investigation. Compelling clinical data suggest that epidural analgesia is given. The mechanism of this is unexplored. I am investigating the role of neural pathways in modulating systemic responses to inflammatory insults.
Index words: transfusion, neutrophils, epidural analgesia.




Subspecialty: Plastic Surgery
Department: Surgery
Name (l,f): Edstrom, Lee
Faculty Research Website: http://research.brown.edu/myresearch/Lee_Edstrom
Location: RI Hosp.
Telephone: 331-2303
General Research Area: Skin flap physiology; microvascular blood flow
Type of projects available: Fetal wound healing; small joint reconstruction; growth factors; melanoma; anatomic studies; artificial skin substitutes
Measurement of prostoglandins in acutely raised canine ventral flaps before and after thromboxane inhibition
Influence of in utero cleft palate repair on facial growth; role of a growth factor-impregnated drug delivery system on wound healing; use of a porous polyethylene implant for small joint reconstruction; cadaver studies of the human wrist.
Course Credit: Yes
Description if different from above: Type of projects (continued): Influence of vitamin A on melanoma growth and metastasis; development of a bilayer organotypic skin substitute for allograft use in burn patients; reconstruction of frontal sinus fractures in a rabbit model

Interested students should contact Dr. Jeff Weinzweig, Department of Plastic Surgery, pager 784-0324, email: scalpels@aol.com

Faculty Research Summary: LEE EDSTROM, M.D.
Dept. of Surgery

Professor, Dept. of Surgery

The Department of Plastic Surgery welcomes the participation of interested students with significant research experience or none at all. Our facilities include a fully-equipped cell culture laboratory as well as microsurgery laboratory. Operating room facilities for large animal surgery (dogs, pigs, primates, sheep) are available within our research building at Rhode Island Hospital as well as within the Biomedical Science building on the Brown University campus. In addition to funding provided by Rhode Island Hospital, three projects are currently funded, in part, by grants from the Plastic Surgery Educational Foundation. Ample funding is provided by clinical income, industry, private donors, and grants from professional societies.

Data stemming from projects conducted this academic year have already resulted in presentations, or acceptances for presentations, at the Plastic Surgery Research Council, the American Society of Plastic and Reconstructive Surgery, the Senior Residents' Conference (where we received the First Prize for the best basic science paper), and the New England Society of Plastic and Reconstructive Surgery.

Students involved in projects within our research program are introduced to, and allowed to participate in, every aspect of research project design, data analysis, surgery, writing of scientific abstracts and papers, and presentation at conferences. Research is coordinated by Dr. Jeff Weinzweig.
Volunteer (academic year): Yes
Summer: Yes
Index: Surgery, inflammation, Plastic surgery; fetal surgery; wound healing; microsurgery; artificial skin; implants



Subspecialty: Orthopaedic Surgery
Department: Surgery
Name (l,f): Green, Andrew
Faculty Research Website: http://research.brown.edu/myresearch/Andrew_Green
Location: RIH
Telephone: 457-1515
Email:agshoulder@aol.com
General Research Area: Shoulder and elbow surgery
Type of projects available: Outcome studies related to a variety of shoulder and elbow disorders; Biomechanical evaluation of rotator cuff repair fixation
Comments:There are a variety of research opportunities both independent and in conjunction with orthopaedic surgery residents in training. Course Credit: No


Volunteer (academic year): Yes
Summer: Yes
Index: Shoulder surgery; elbow surgery.


Subspecialty: Biomedical Engineering
Department: Surgery
Name (l,f): Kim, Hae Won
Faculty Research Website: http://research.brown.edu/myresearch/HaeWon_Kim
Location: Miriam Hosp.
Telephone: 793-4510
General Research Area: Applied physiology/biochemistry
Type of projects available: Laboratory work with small animals/in-vivo and in-vitro evaluation
Laboratory work with small animals/speciman processing analysis
Course Credit: Yes

Faculty Research Summary: HAE WON KIM, Ph.D.
Dept. of Surgery

Assistant Professor, Dept. of Surgery, Miriam Hospital

Research Summary: The development and evaluation of red cell substitutes for use in treating shock and other hypovolemic situations. Emphasis is on stroma free hemoglobin, function-structure, metabolism O2 delivery characteristics and chemical modification. Design of expert systems to determine transfusion requirements. Role of immune system in transfusion and shock resuscitation.

Volunteer (academic year): Yes
Summer: Yes
Index: Cardiovascular System, Physiology, Blood


Subspecialty: Pediatric Surgery
Department: Surgery
Name: Luks, Francois
Faculty Research Website: http://research.brown.edu/myresearch/Francois_Luks
Location: RI Hosp (Biomed, 3rd floor)
Telephone: 421-1939
General Research Area: Endoscopic fetal surgery; endoscopic tracheal obstruction in fetal lamb model to promote lung growth
Type of projects available: Fetal tracheal obstruction in sheep; daily postoperative tracheal fluid sampling, pressure measurements, fluid analysis for growth factors, growth factor binding proteins; modulation of lung growth by modifying tracheal fluid compostion, pressure, flow, etc. Title(s): "The molecular mechanisms behind fetal lung growth post tracheal ligation"; "Accelerated fetal jung maturation induced by tracheal ligation: analysis of cytokines and growth"
Course Credit: Yes

Faculty Research Summary: FRANCOIS LUKS, M.D.

Model for endoscopic fetal surgery in sheep.
Application: minimally invasive alternative to open fetal surgery in human.

Endoscopic tracheal obstruction to promote lung growth in fetal lamb:
AIMS: 1) Develop the model of endoscopic obstruction. Application: to treat pulmonary hypoplasia associated with congenital diaphragmatic hernia, by promoting lung growth. Tracheal obstruction causes lung growth, which will gradually reduce viscera back into the abdomen. By performing this antnatally, the hope is to have a baby with diaphragmatic hernia born with normal lungs, thereby improving the current 60% mortality rate. 2) Understand the mechanisms of fetal lung growth secondary to tracheal obstruction, by analyzing tracheal fluid, measuring intratracheal pressure following obstruction, and modulating tracheal pressures ad fluid composition.
Summer: Yes
Index: Fetal surgery, Lamb, Lung Development, Diaphragmatic Hernia, Pediatric Surgery



Subspecialty: Transplantation
Department: Surgery
Name: Morrissey, Paul
Faculty Research Website: http://research.brown.edu/myresearch/Paul_Morrissey
Location: RI Hosp, APC 921
Telephone: 444-5285
Email:pmorrissey@lifespan.org
General Research Area: kidney transplantation, organ donation
Type of projects available: 1. Living Donors - 200 Donor Evaluations: outcomes, exclusions, CTA, unexpected pathology
2. Long-term follow-up after donor nephrectomy
3. Racial Disparities in Living Kidney Donation (Tx 82:876). Evaluation ˆ how many present, evaluate, excluded (reasons). Race, time to Tx, etc
4. DCD ˆ experience (in depth outcome review ˆ Seth Karp)
5. Neosynephrine ˆ effects on renal perfusion (urine output)
6. Cigarette Cessation ˆ intervention for ESRD and Transplant patients
7. Good Samaritan Donors: Behavioral studies, public awareness, public policy, „advertising‰ (promotion)
8. NEOB - Influence of the circumstances of death vs. race (young traumatic, less likely than CVA, e.g.); Bob Wolfe data (Eligible Death Study)
9. NEOB - Changing nature of DD in the NEOB (2000-2004 donors versus 1990-1994 donors ˆ risk factors, age, serologies, CNS CA, IVDA.)

Course Credit: Yes
Research Summary: Brown Program in Transplantation Research

Scope of Projects
- Clinical trials (Single center, multi-center, Pharmaceutical industry)
- Retrospective chart review
- Prospective studies
- NEOB-related (regional) studies
Who should participate?
- Brown Medical Students (Summer Research Assistantship, SRA)
- Brown Undergraduates (UTRA or SRA) Project goals
- Poster presentation (RIH, Brown, local meeting, national meeting)
- Oral presentation
- Scientific paper
- Thesis
Funding - Ultimate gift fund
- Travel award (oral presentation)
- Brown stipend (UTRA, SRA)

Volunteer (academic year): Yes
Summer: Yes
Index: Kidney transplantation: organ donation, donor and recipient outcomes, polyoma (BK) virus, immunosuppression, Dialysis access surgery.



Department: Surgery
Name: Reichner, Jonathan
Faculty Research Website: http://research.brown.edu/myresearch/Jonathan_Reichner
Location: RI Hospital
Telephone: 444-8683
General Research Area: (1)Cancer research
(2) Inflammation
Type of projects available: Titles(s): "The role of interleukin-6 in cancer metatasis"; "The role of integrins in neutrophil migration"
Course Credit: Yes

Faculty Research Summary: JONATHAN REICHNER, PH.D.
Ph.D., SUNY Buffalo, 1983. 444-8683. Jonathan_Reichner@brown.edu

Research Summary: (1) Cancer Research: The most difficult aspect in treating cancer patients resides in the fact that malignant tumor cells can separate from the original tumor and establish new tumors in distant sites throughout the body, a process known as metastasis. The metastitic spread of cancer is the reason that removal of the primary tumor does not often cure the disease. Many studies have now shown that not all cells within the primary tumor have the capacity to metastisize, it is a phenotypic trait acquired by relatively few cells. Researchers are now trying to identify genetic differences between tumor cells that are capable of metastasis and those that are not in the hope of eventually designing a therapeutic approach that could intervene in the process. To study the metastatic process, my laboratory has developed rat cell lines of liver cancer (hepatocellular carcinoma) which differ in their ability to metastasize. We found that the highly metastatic cells produced interleukin-6, whereas the poorly metastatic cells did not. To determine if IL-6 was itself a sufficient genetic alteration to convert a non-metastatic cell to a metastatic cell, they used recombinant DNA techniques to insert the IL-6 gene into the poorly metastatic cells (LO-LI-6). When tested, these new constructs were found to be highly metastatic. Interleukin-6 is not normally thought to be involved in tumor cell behavior, it is a hormone associated with antibody production by B cells and in a clinical condition known as the acute phase response. The acute phase response is a reaction to severe injury such as trauma, burns, and sepsis characterized by fever, variations in vascular permeability, and changes in the biosynthetic properties of many organs, particularly the liver. Exactly how IL-6 increases metastasis is now being investigated. That is, IL-6 may exert local effects at the site of the original tumor, an action that might be exerted directly on the tumor cells themselves or on the surrounding stroma and inflammatory cells within. In addition, IL-6 may effect the hot in a systemic fashion which may indirectly effect the metastatic potential of the tumor. (2) Inflammation: Localization of circulatory polymorphonuclear leukocytes (PMN) to extravascular sites of inflammation is a function of repeated adhesive and de-adhesive events. Following extravasation, PMN migrate towards a source of inflammation in response to locally elaborated chemotoxins and cytokines. Stimulated by a chemotactic gradient, PMN traverse extracellular matrix (ECM) by way of transient interactions between integrin receptors and components of the ECM which serve as adhesive ligands. Integrin receptors reported to contribute to the process of neutrophil locomotion include members of the Beta 2 (LFA-1 and Mac-1) and Beta 1 subfamilies (VLA-4,5,6). Mac-1 (CD 11b/CD18, CR3, Mo-1) is a multifunctional receptor most prominently expressed on myeloid and natural killer cells. Structurally classified as an adhesion moleculr, with particular relevance to cell-mediated interaction with extracellular matrix, recent investigations identify Mac-1 participation in a variety of cellular functions. Mac-1 is unique among the Beta 2 integrins in that it contains a lectin site capable of interacting with N-acetyl-D-glucosamine, glucose, and possible mannose residues. Moreover, recent reports describe regulation of Mac-1 function through binding of soluble Beta-glucan to the lectin site. Specifically, Beta-glucan has been shown to induce cytoxicity in natural killer cells for iC3b-opsonized target cells which were otherwise resistant to killing. Based upon evidence that interaction of soluble Beta-flucan with Mac-1 results in altered effector cell behavior, the possibility tha the regulatory effect of Beta-glucan extends to additional integrin-mediated functions was examined. The current investigation tests the hypothesis that in the context of extracellular matrix, Beta glucan alters the migratory behavior of neutrophils.

Publications: Yauch, R.L., Berditchevski, F., Harler, M.B., Reichner, J.S., and Hemler, M.E. Highly stoichiometric, stable and specific association of integrin a3ß1 with CD151 provides a major link to phosphatidylinositol 4-kinase, and may regulate cell migration. Molecular Biology of the Cell 9: 2751-2765, 1998.
Harler, M.B., Wakshull, E., Filardo, E.J., Albina, J.E. and Reichner, J.S. Promotion of neutrophil chemotaxis by ß-glucan through differential regulation of ß1 and ß2
integrins. Journal of Immunology 162:6792-6799, 1999.
Albina, J.E. and Reichner, J.S. Role of nitric oxide in mediation of macrophage cytotoxicity and apoptosis. Cancer and Metastasis Reviews17:39-53, 1998.
Summer: Yes
Index: Cancer, Metastasis, Rat, Liver, Neutrophils, Inflammation, Beta-glucan, Migration, Integrins



Subspecialty: Urology
Department: Medicine
Name (l,f): Sigman, Mark
Faculty Research Website: http://research.brown.edu/myresearch/Mark_Sigman
Location: RIH
Telephone: 444-8570
General Research Area: Human testis and sperm physiology
Assessment of stem cell factor in infertile men
Type of projects available: Title(s): "Fluorescent in situ hybridization; "Cytogenetic assay for genotoxicity testing of environmental toxins"; "Optimization of acrosomal status of human sperm";
Course Credit: Yes
Description if different from above: Learn basics of semen analysis, sperm processing and assesment of human sperm production.

Faculty Research Summary: MARK SIGMAN
Department of Medicine
Research into etiology and treatment of the infertile male.

Volunteer (academic year): Yes
Summer: Yes
Index: Spermatozoa, Male Infertility, Spermatagenesis, stem cell factor


Subspecialty: Pediatric surgery, pediatric liver disease
Department: Surgery
Name: Tracy, Thomas, Jr.
Faculty Research Website: http://research.brown.edu/myresearch/Thomas_Tracy
Location: RI Hosp. (Hasbro Hosp.)
Telephone: 444-7605
General Research Area: Liver regeneration, liver repair, liver fibrosis, matrix metalloproteinase gene expression
Type of projects available: Cellular and molecular mechanisms of liver repair following biliary decompression, neonatal cholestasis, biliary artesia, hepatic stem cells in injury and repair, and hepatic mecrophage activation
Course Credit: Yes
Description if different from above: Students receive an outstanding exposure to cellular and molecular biology of liver research, numerous clinical studis are present whin the filed of pedi surgery with a specific focus on pedi and neonatal disease.

Faculty Research Area: THOMAS TRACY, JR., M.D.

Professor of Surgery and Pediatrics. email: Thomas_Tracy@brown.edu

Research Summary: At critical points in chronic lever injury, the potential for liver repair is lost. Timely surgical and medical treatment however, initiates liver repair in infants, children and adults, interrupting the cycle of inflammation and hepatic fibrosis. The subsequent cellular regulation of matrix protein degredation and resolution of injury dependent fibrosis is unknown. The long-term goals of our studies are to define the molecular mechanisms required for ordered matrix resorption and liver repair without scar. Specific aims have been designed to test the hypothesis that repair, resolution of scar, and the restoration of hepatic architecture depend on coordinated regulatory mechanisms of matrix degradation through matrix metalloproteinase (MMPP and tissue inhibitor of MMP (TIMP) gene expression, cellular localization and most importantly, biologic activity. Further, we propose that Kupffer cells (KC), the resident macrophage population, have a central role in the inflammatory and fibrogenic regulation of liver repair after chronic injury. Specific Aim I addresses the molecular and cellular mechanisms of reversible hepatic fibrosis and those of delayed matrix resorption. A unique rat model of reversible biliary obstruction will simulate early, intermediate, and late, near end stagecholestatic liver injury. This model allows biliary decompression to initiate liver repair. The effect of injury duration on matrix (Collagen I, III, IV, elastin, laminin), MMP (1,28,9,13,14) and TIMP (1,2) mRNA and protein expression will be measured in whole liver and cells using new methods of laser capture microdissection. Changes in these profiles will be directly applied to the mechanism of matrix resorption by simultaneous measurement of MMP activity by in-gel and in situ zymography. Specific Aim 2 mechanistically tests the hypothesis that KC are in vivo regulators of matrix metabolism. Through strategies of KC depletion/inactivation by gadolinium or Dexa-Man10-HSA targeted dexamethasone during repair, matrix resorption, regulatory cytokine profiles and MMP-TIMP activity will be localized in cells and measured. In Specific Aim 3 we will establish the effect of progressive injury on the in vitro capacity of isolated hepatic macrophages to express specific MMP and dibrogenic/antifibrogenic cytokine (TGF beta, IL1, 6, 10) profiles during repair. KC inactivation and MMP stimulation/suppression strategies will isolate the net collagenolytic activity of hepatic macrophages. Apart from broad clinical implications for the treatment of cholestatic or other chronic liver diseases, these studies have the significance to be the first studies to identify key molecular mechanisms for successful repair after progressive liver injury. They have the potential to yeield targets for therapy to promote liver repair or rescue patients approaching end stage liver disease.

Volunteer (academic year): Yes
Summer: Yes



Subspecialty: Critical Care Medicine
Department: Surgery
Name: Yodice, Paul
Faculty Research Website: http://research.brown.edu/myresearch/Paul_Yodice
Location:Miriam Hosp.
Telephone: 793-4501
General Research Area: Intensive care, sepsis, cytokines, acute respiratory distress syndrome (ARDS)
Title(s): "Neutrophil rheology in sepsis"
Course Credit: Yes
Faculty Research Summary: PAUL YODICE, M.D., F.A.C.P.

Research Summary: Sepsis is an overwhelming infection with a mortality of 50% despite advances in antibiotics and life support. One of the major contributors to this mortality is altered microvascular blood flow resulting in tissue hypoperfusion and hypoxia. Previous work has revealed that neutrophils may actually contribute to tissue oxygen debt by occluding capillaries. non-stimulated, PMN's are deformable and can easily pass through blood vessels which are actually smaller in diameter than the cells themselves. The systemic inflammatory response of sepsis results in cytokine production which has a profound effect on neutrophil deformability, aggregation and adherence. Teleologically, this aids in maintaining the cells in the area of infection (the skin on your arm for example) so that they may fight the infection. Under circumstances of severe infection, these same cytokines may cause a global response and leukocytes may become fixed in otherwise healthy areas and cause tissue oxygen starvation and death. We have designed several studies in which neutrophils are isolated from healthy subjects and exposed to the cytokines most likely to alter rheology. Measurements of both level and duration of incubation necessary to induce the changes observed in sepsis would be then obtained. With this information, perhaps we can begin to identify agents to prevent this normal immune response from becoming the generalized inflammation that leads to tissue oxygen debt and ultimately patient death. We have, based upon the research done this pat year with graduating student Jeffrey A. Hsu, submitted to abstracts to the critical care journal CHEST for presentation and publication this year.
Volunteer (academic year): Yes
Summer: Yes
Index: Human Sepsis, Septic Shock, Cytokines