Division of Trauma and General Surgery
Research and Clinical Trials
University of Pittsburgh Medical Center:
Nearly all members of the Department of Surgery engage in clinical and/or laboratory research. Faculty interests cover a wide spectrum of subjects, including surgical metabolism; cardiovascular and gastrointestinal physiology; transplantation; mechanical circulatory assisting devices; surgical techniques and equipment, such as membrane oxygenation or stapling devices; studies of hemorrhagic and septic shock; and surgical oncology. Resident participation in independent, ongoing research projects is strongly encouraged, and the program is designed to provide special experience and training for those interested in academic surgery.
Research takes place in core and shared facilities in the Biomedical Science Tower, UPMC Montefiore, Scaife Hall, and the Biotechnology and Bioengineering Center. Collaborations exist among the divisions of the department of surgery. Multi-disciplinary centers include:
- The University of Pittsburgh Cancer Institute (UPCI): The section of Surgical Oncology participates actively with the University of Pittsburgh Cancer Institute. Members of the Department co-head the Pittsburgh Cancer Institute programs of gastrointestinal oncology, urologic oncology, and biologic oncology. Surgery faculty are active in all other programs at UPCI.
- The Pittsburgh Genetics Institute: Several faculty members hold co-appointments in the Department of Molecular Genetics and Biochemistry. We are leaders in ongoing programs in genetic screening endoocrinology, vascular disease, breast cancer, oncogeny research and gene therapy. Most clinical operative gene therapy protocols at the University of Pittsburgh are centered in the Department of Surgery.
- The University of Pittsburgh Artificial Heart Institute, initiated by surgical faculty members, has become a designated surgical training center for bioengineering technologies and has become an incubator for spinoff companies.
- The Nuclear Magnetic Resonance Center (NMR): a joint program of Carnegie Mellon University and the University of Pittsburgh. Several collaborative projects are centered there.
- Bioengineering is a joint program of the School of Engineering, Surgery and Orthopedics. Research studies are well supported, and the program has generated numerous life-enhancing inventions.
- The Transplantation Institute, re-named in 1995 the Starzl Institute for Transplantation: has developed as a transplant division in the Department of Medicine, but continues to enjoy the co-support of the Department of Surgery.
Mission & Goals
The mission of the Department of Surgery is threefold:
- To provide the best possible care to patients who require surgical services in the areas of general surgery, cardiothoracic surgery, pediatric surgery, urological surgery, vascular surgery, transplantation surgery, and wound healing.
- To provide state of the art educational programs in all areas of clinical surgery and in the biologic basis of surgical illness.
- To produce new information from its research programs which will contribute to the practical solutions and theoretical structure of future surgical practice.
Because these three goals are equally important and mutually interactive, the members of the department are expected to be supportive of and demonstrate all three.
The Department of Surgery is designed to provide an environment in which all three goals can be pursued simultaneously. The department gains strength in its mission from its collegial relationship with other clinical and basic science departments within the medical school, the health science schools, and the entire university community.
To fulfill our missions, we have set the following goals:
- To support the efforts of UPMC Health System affiliated hospitals to succeed in the managed care environment by aiding efforts to minimize cost of care and maximize service productivity.
- To continue to recruit to the department new faculty members whom, in the aggregate, provide balance between administrative know-how, leading-edge practice, superb teaching, and innovative research. To retain faculty members who are at risk of recruitment by competitors.
- To promote the growth and development of research programs which integrate into surgical practice the advances in cellular and molecular biology and bioengineering.
- To encourage the development of interdisciplinary clinical, research, and teaching programs between divisions, departments, and schools, and extending to other universities and industries.
Billiar Lab
The main research interest of our laboratory is the regulation and function of inducible nitric oxide synthase (iNOS).
Other interests include apoptosis, gene therapy, hypoxia, shock, inflammation and liver disease.
We are a productive and well-funded lab with both PhDs and MDs working together in a coordinated fashion for the pursuit of knowledge and the advancement of science.
Administration
Timothy R. Billiar, MD
Kathy DiGiacomo, Lab Secretary
Phone: 412-647-5609
E-mail: digiacomok@upmc.edu
Location: NW607 MUH
Dates: October 1999-present
Provides administrative support for all our investigators and their lab staff. Also is involved as a source of administrative support for the Sepsis Simulation group. Hobbies include watching her son coach football, reading, and hanging out with family and friends.
Richard A. Shapiro, BS, Research Instructor
Phone: 412-647-5288
E-mail: rashapir+@pitt.edu
Location: NW605 MUH
Place of Training The University of Pittsburgh
Dates: 1992-present
Projects: 1. Human iNOS gene regulation. 2. CD14 gene regulation and expression. Hobbies include base jumping.
Projects
Hemorrhagic Shock
Vital organ injury and dysfunction in hemorrhagic shock stems from a systemic inflammatory response. Unlike sepsis, the systemic inflammation after hemorrhagic shock is not due to a specific site of infection. Instead, other stimuli activate inflammatory pathways. Examples include hypoxia, release of circulating factors such as hormones or changes in flow which are sensed locally and initiate signaling cascades. We have previously shown that several genes, include the inducible nitric oxide synthase (iNOS), CD14, and COX-2 are all upregulated during shock alone. These findings initiated a search for the upstream signaling pathways involved in the activation of gene expression during shock.
Sepsis
Sepsis following trauma or major surgery results in prolonged and expensive intensive care unit hospitalization and remains a major cause of mortality. It is estimated that approximately 500,000 patients develop sepsis, or which 175,000 die. Surgical sepsis is most often caused by bacterial infection, and even more specifically by Gram-negative bacterial infections, though Gram-positive bacterial sepsis is also a serious clinical problem with distinct features. The host recognizes the presence of bacterial infections through multiple mechanisms, involving both elements of the adaptive immune response (e.g. antibodies and complement; T-cell responses to bacterial superantigens) as well as elements of the innate immune response. The innate immune response has evolved to recognized so-called “molecular patterns” on microbes, rather than the antigenically distinct structural elements recognized by antibodies or by T-cell receptors in the context of major histocompatibility molecules. On Gram-negative bacteria, the main stimulant of the innate immune response is endotoxin (lipopolysaccharide: LPS), whereas mammalian hosts recognize a diverse group of Gram-positive bacterial macromolecules including lipoarabinomannan (LAM), peptodoglycan (PGN), lapidated outer surface protein of Borrelia burgdorferi (OspA), and lipoteichoic acid (LTA). Other bacterial “molecular patterns” include N-formyl methionylated peptides and CpG DNA. This bacterial recognition system relies on cell surface receptors that are highly conserved throughout evolution, members of the Toll-like receptor (TLR) family. This extremely sensitive system appears designed to detect elevated levels of local or circulating microbial products and rapidly initiate an antimicrobial response. Upon detection of microbial products by the CD14/TLR system, the host elaborates numerous pro-inflammatory cytokines leading to the upregulation of adhesion molecules, the accumulation of leukocytes, and the production of powerful effector mechanisms, including the free radicals superoxide and nitric oxide (NO).
Apoptosis
The effect of nitric oxide on cell viability differs based on the degree of redox stress; additionally, different cell types differ considerably in their response to nitric oxide. In macrophages, pancreatic islet cells, neurons, enterocytes, thymocytes, cardiac myocytes, endothelial cells, and fibroblasts, even low level NO lead to apoptosis. In contrast, B lymphocytes, natural killer cells, eosinophils, embryonic motor neurons, pheochromocytomas, ovarian follicles, and hepatocytes can be protected by NO against apoptosis included in various ways. Hepatocytes are unique in that not only are these cells protected by NO but also necrotic death is not see until the cells are exposed to supraphysiologic concentrations of NO donors in the millimolar range.
No Function
The chemical fate of NO in cells remain the topic of considerable debate due, in large part, to the complexities associated with measuring the abundance of short-lived radicals. It is reasonably well accepted that NO with its one unpaired electron, will react avidly with oxygen, superoxide anion radical (02), and transition metals. These reactions can lead to the modification of proteins, resulting in the activation or inactivation of enzymes, or lead to cellular toxicity through various other means. It is also safe to conclude that the chemistry resulting from these interactions can be separated in nitrosation or oxidation. The challenge in the field has been in defining the pathways to nitrosation or oxidation in intact tissue.
Cell Signalling
We have published that levels of NO sufficient to activate soluble guanylyl cyclase prevent apoptosis induced by growth factor withdrawal in PC-12 neuroblastoma cells. This protective effect of NO was lost when cGMP synthesis was inhibited. Cell permeable cGMP analogs are highly protective against apoptosis in hepatocytes. Others have shown that camp protects hepatocytes from bile salt-or FasL-induced apoptosis and liver ischemia/reperfusion injury. These observations led us to test the protective effect of cell-permeable cAMP is emerging as an important survival signal in hepatocytes. Based on this and the similarities between cGMP and cAMP in preventing apoptosis, we have extended the scope of our research to include cAMP.
iNOS Regulation
Our focus for many years concerns the regulation and function of iNOS in the liver. The enzyme is readily upregulated in HC, as our laboratory first showed in 1989. Moreover, human iNOS was first detected in and cloned from HC. In vivo studies have shown that the consequences of iNOS upregulation in liver are dependent upon the specific physiological or pathological circumstances. Following conditions associated with severe redox stress, iNOS contributes to hepatocellular damage as seen in hemorrhagic shock or hepatic ischemia/reperfusion. In other settings, induced NO is anti-apoptotic in the liver. Factors that govern the consequences of iNOS in the liver are poorly understood, but clearly cells such as HC need mechanisms to regulate iNOS activity in order to maximize the protective actions while limiting toxicity.
Location
The laboratory is located on the main campus of the University of Pittsburgh at Montefiore University Hospital (MUH). This modern building houses a variety of laboratories, offices, and conference rooms for both basic and clinical investigators and is connected to the UPMC via a skywalk.
Map of the University of Pittsburgh campus
Positions Available
We are continually recruiting highly motivated individuals who are interested in pursuing a post-doctoral fellowship position in this laboratory. We are a well-funded laboratory, offering research positions for MDs and PhDs who are supported by both an NIH training grant as well as other sources.
Interested people are encouraged to apply.
Send a letter of intention as well as a CV to:
Timothy R. Billiar, MD
George Vance Watson Professor of Surgery
F1281 Presbyterian University Hospital
University of Pittsburgh
Pittsburgh, PA 15261
412-647-1749
Contact Us
For general questions about the lab or inquiries about positions available, contact:
Deb Williams, BA
NW 607 MUH
3459 Fifth Avenue
Pittsburgh, PA 15261
Phone: 412-647-5609
Email: williamsd8@upmc.edu
Bio:
Title: Research Administrator
Dates of Employment: 5/1989 to present
Degree: BS in Natural Sciences
Place of Education: University of Pittsburgh
Projects: Manage and oversee all laboratory day to day functions.
For technical questions, contact:
Richard A. Shapiro, BS
NW 607 MUH
University of Pittsburgh
Pittsburgh, PA 15261
Phone: 412-647-5609
Email: rashapir+@pitt.edu
Bio:
Title: Research Instructor
Date of Employment: 1/2/92 to present
Place of Education: University of Pittsburgh
Research Projects: 1. Molecular Biology 2. Recombinant Protein Purification - HMGB1, TOLR4, MD2
Course descriptions and program requirements are subject to change.