McGowan Institute?
November 2005 | VOL. 11 | www.McGowan.pitt.edu
University of Pittsburgh transplant pioneer Thomas E. Starzl, MD, PhD, has been named recipient of the 2004 National Medal of Science, the nation’s highest scientific honor. Dr. Starzl, distinguished service professor of surgery, University of Pittsburgh School of Medicine and director emeritus, Thomas E. Starzl Transplantation Institute at the University of Pittsburgh Medical Center, and seven other medal laureates will receive the awards from President George W. Bush in a White House ceremony in the near future.
Dr. Starzl’s groundbreaking work in organ transplantation has spanned more than four decades and has earned Dr. Starzl the distinction as the father of transplantation, and Pittsburgh the moniker transplant capital of the world.
Dr. Starzl performed the world’s first liver transplant in 1963 while at the University of Colorado. Four years later, he performed the first successful liver transplant. In 1980, he brought the field a step forward when he introduced the new anti-rejection medications anti-lymphocyte globulin and cyclosporine, which became the accepted transplant regimen for patients with liver, kidney and heart failure.
In 1981, Dr. Starzl joined the University of Pittsburgh School of Medicine and led the team of surgeons who performed the city's first liver transplant. Thirty liver transplants were performed that year, launching the university's liver transplant program – the only one in the nation at the time – and invigorating the university's heart and kidney transplant programs. In 1989, Dr. Starzl introduced the anti-rejection medication FK506, which markedly increased survival rates for liver and other organ transplants and led the way to other successful types of organ transplants, including pancreas, lung and intestine.
Today, Dr. Starzl remains active in research, mapping the relationships between donor and recipient cells and developing new therapeutic strategies to achieve immune tolerance after transplantation with a much lower risk of side effects from immunosuppressive therapy.
Established by Congress in 1959, the National Medal of Science is the nation’s highest honor for American scientists and is awarded annually by the President of the United States to individuals “deserving of special recognition for their outstanding contributions to knowledge.”
$2,000 Award for a Student Author
Acta Biomaterialia has announced the Annual Student Author Award which will provide $2,000 to the wining student author. The following highlights the eligibility and application criteria. For additional details, click here.
- The awards are limited to candidates whose work is reported in Acta Biomaterialia and who were bona fide graduate students at the time the work was performed.
- The candidate for the award must have made the major contribution to the work reported.
- Any student author of a paper published in Acta Biomaterialia during any one calendar year is eligible for an award in the following year. The article must appear in an issue for that calendar year. Publications appearing online have eligibility based on the year in which they appear in hardcopy.
- The candidates should be nominated by their research advisor or a senior member of their faculty.
- Candidates should submit their letter of nomination, together with two supporting letters and their curriculum vitae.
- Students who have written a single-author paper are also required to submit the same letter of nomination and supporting letters.
- Nominations based on manuscripts published in Acta Biomaterialia during the calendar year, January-December, 2005, must be submitted by March 31, 2006 to:
William R. Wagner, Ph.D.
Editor, Acta Biomaterialia
McGowan Institute for Regenerative Medicine
University of Pittsburgh
100 Technology Drive, Suite 200
Pittsburgh, PA 15219 USA
A research team under the leadership of Charles McTiernan, Ph.D., has found that a gene vector carrying an inhibitor of metalloproteinase-2 (MMP-2), a protein shown to stimulate adverse healing in heart tissue after a heart attack, protected experimental mice against further cardiac damage and subsequent death.
Furthermore, the benefits correlated with a partial restoration of the normal ratios between metalloproteinase-2 and its specific inhibitor, known as tissue inhibitor of metalloproteinase-2 (TIMP-2).
“Induction of metalloproteinases has been shown to contribute to adverse remodeling of cardiac tissue after myocardial infarction,”according to Dr. McTiernan. “It has been hypothesized that supplementing post-MI tissue with TIMP-2 can normalize the balance of metalloproteinases and their specific inhibitors and protect against the damage of myocardial infarction.”
To determine if gene therapy could be used to improve outcomes following a heart attack, Dr. McTiernan and his coworkers gave one group of mice with experimental myocardial infarctions (MI) an injection of viral particles containing the TIMP-2 gene and compared their outcomes to untreated MI and control mice. The investigators then assessed the left ventricular size and function of the surviving mice seven days after their myocardial infarction and also measured MMP-2 and -9 and TIMP-1 and -2 protein levels.
A new type of immunotherapy in which dendritic cells are tricked into action against cancer when they are exposed to harmless pieces of viruses and bacteria is described in the November issue of Cancer Research. Dendritic cells, the pacemakers of the immune system, are known to play a vital role in the initiation of the immune response but are often eluded by cancer.
In the paper, Louis D. Falo, M.D., Ph.D., and his colleagues describe the creation of an animal model of an immunotherapy approach that, first used in cancer patients, uses a patient’s own tumor cells to stimulate anti-tumor immunity. The discovery of the animal model will enable researchers to more fully understand and develop the approach.
In the study, melanoma cells and dendritic cells from mice were removed, combined together in a culture dish and exposed to pieces of viruses and bacteria. The researchers used the most aggressive mouse melanoma tumor, B16, which has multiple mechanisms to escape the immune system that are similar to those used by human cancers. They found that the dendritic cells were able to extract antigens directly from tumor cells. By exposing the antigen-bearing dendritic cells to harmless pieces of bacteria and virsuses that they preceived as dangerous, the researchers “tricked” them into recognizing the tumor as dangerous as well. The alerted cells were then injected back into the mice where they successfully activated a particular T-cell response important for fighting tumors. That response, called Th1, led to a significant reduction in tumor growth in the mice.
The research team further discovered that the Th1 response was enough to stop tumor growth on its own, indicating the importance of Th1-type immunity for tumor therapy. Prior to their discovery, researchers believed that a Th1 response was important, but that it worked primarily by activating another type of T-cell called a cytotoxic T-cell (CTL). These results suggest that it may be important to monitor Th1-type immunity in addition to CTL immunity when evaluating patients’ responses to immunotherapy.
Melanoma is the most serious form of skin cancer. Although it accounts for only 4 percent of all skin cancer cases, it causes most skin cancer-related deaths. Lymphomas of the skin, including cutaneous T-cell lymphomas, are diagnosed in approximately 16,000 to 20,000 people in the United States each year and are often difficult to diagnose in early stages.
This study was funded by a grant from the National Cancer Institute. Collaborators on the study include University of Pittsburgh researchers David A. Hokey; Adriana T. Larregina, M.D., Ph.D.; Geza Erdos, Ph.D.; and Simon C. Watkins, Ph.D.
New Grant Awards
| Grant: | Bioengineering & Biologic Studies of Aneurysm Weakening |
| PI: | David A. Vorp, PhD |
Fifteen thousand Americans die each year from AAA rupture, making it the 13th leading cause of death in this country. Enlargement of AAA is preceded by failure of the elastin and loading of the collagen in the aortic wall. Extracellular matrix (ECM) degeneration continues as the aneurysm enlarges. We have demonstrated that the strength of the AAA wall is also progressively decreased as it enlarges. The AAA will rupture when the strength of the tissue is reduced below the mechanical stress placed on the wall by the intraluminal pressure. Clearly, wall strength and structural integrity play an important role in the natural history of AAA. To understand this natural history, the mechanisms behind wall weakening must first be elucidated.
Dr. Vorp’s lab will study two carefully hypothesized mechanisms of AAA wall weakening by utilizing state-of-the-art, validated bioengineering and biologic methods. Preliminary work in the Vorp Lab shows that the stress distribution in the AAA wall is quite variable, with regions of high stress concentrations. Also shown is that the commonly found intraluminal thrombus (ILT) within AAA attenuates diffusion of O2 to the AAA wall. A thick layer of ILT may cause hypoxia of the adjacent wall. Our hypothesis is that the strength of the AAA wall is regionally reduced as a direct result of local stress concentrations and this is further augmented by hypoxic conditions. These hypotheses will be addressed by studying freshly excised AAA tissue from regions with known stress levels and from aneurysms with thick and thin layers of ILT. The microstructure of the tissue will be assessed along with expression of genes related to either degradation or maintenance of wall integrity, such as matrix metalloproteinases and ECM precursors tropoelastin and procollagen. The results of this study could have an immediate impact on the clinical management of AAA.
Demonstration that wall strength is reduced by focal concentrations of wall stress or by ILT-induced mural hypoxia would allow clinicians to evaluate AAA in a more biophysically sound manner. Additionally if the mechanisms behind this weakening are elucidated, therapies may be developed to inhibit or reverse them, leaving an adequately strong, dilated aorta with a reduced risk of rupture.
The Co-investigators are Doug Chew PhD, Michel Makaroun MD, Michael Sacks PhD, Simon Watkins PhD, Robert Ferrell PhD, Stephen Wisniewski PhD and, Elena DiMartino PhD
| Grant: | Howard Hughes Medical Institute Grant For Interdisciplinary Doctoral Program In Computational Biology |
| PI: | Ivet Bahar, PhD, and Robert Murphy, PhD |
Carnegie Mellon University, in partnership with the University of Pittsburgh, has received a prestigious grant from the Howard Hughes Medical Institute (HHMI) to support the development of an interdisciplinary joint doctoral program in computational biology.
The $1 million grant, one of only 10 awarded from a competition of 132 applicants nationwide, will support the new Ph.D. program in Computational Biology that was established jointly by the two universities last year. The primary focus will be on curriculum development, emphasizing the development of a new laboratory course for computational biologists and the creation of expanded course offerings in bioimage informatics and computational structural biology.
“HHMI is partnering with the National Institutes of Health’s National Institute of Biomedical Imaging and Bioengineering (NIBIB) to ensure sustaining support as well as start-up funds for the new programs,” according to an HHMI press release issued on November 22. “Following a second competition to ensure that the HHMI-funded recipients achieved their original goals, the NIBIB — committed to integrating the physical and life sciences — will support the second phase of this program, which is aimed at sustaining interdisciplinary graduate education.”
“The HHMI-NIBIB partnership capitalizes on the special strengths of each organization,” said HHMI President Thomas R. Cech. “HHMI can provide flexible support to catalyze development of new interdisciplinary programs, and the NIBIB will sustain these and related programs once they are developed, as NIH does so well with traditional training grants.”
During the first three years, Carnegie Mellon will be the lead institution under the HHMI grant, and then Pitt will be the lead institution during the latter five years under NIBIB funding.
In May 2005, the University of Pittsburgh and Carnegie Mellon, led by professors Ivet Bahar, Ph.D., chair of the department of computational biology at the University of Pittsburgh, and Robert Murphy, Ph.D., professor of biological sciences and biomedical engineering at Carnegie Mellon and program director for the HHMI grant, created a joint doctoral program in computational biology to meet the growing need for graduate-level training in this field. The program enrolled a small number of students in fall 2005 and will accept its first full class in fall 2006. For more information about the joint doctoral program, please visit: www.compbio.cmu.edu.