McGowan Institute?
March 2008 | VOL. 7, NO. 3 | www.McGowan.pitt.edu
McGowan Institute To Welcome Distinguished Lecturer Hirschi
The McGowan Institute Distinguished Lecture Series will welcome Karen K. Hirschi, PhD, on April 3rd, 2008. Dr. Hirschi is Professor of Pediatrics and Molecular & Cellular Biology at the Baylor College of Medicine.
Dr. Hirschi’s topic is “The Study of Vascular Morphogenesis Enables Tissue Engineering” Prior to her appointment at Baylor, Dr. Hirschi was an AHA Postdoctoral Fellow at the University of Arizona and an NIH Postdoctoral Fellow and Instructor at Harvard Medical School. Dr. Hirschi is also the recipient of two significant awards from the American Heart Association: the Beginning Grant-In Aid for Junior Investigators (1998-1999) and the Established Investigator Award (2004 to 2009).
The lecture will be held on April 3, 2008 in Scaife Hall, 4th Floor, Auditorium 5, at 4:00 pm. A reception and Molecular Art Exhibit will follow in BST South 100.
The featured artist is Ericka Fink, MD, who is in the Department of Critical Care Medicine at the Children’s Hospital of Pittsburgh.
The McGowan Institute for Regenerative Medicine (MIRM) held its 2008 Retreat March 10-12, 2008. The focus was on peer-to-peer networking and on opportunities to explore collaborative ventures. Collaborative partnerships are necessary to facilitate the rapid clinical implementation of new advances. The leadership team at MIRM also gained insight in the realization of MIRM’s mission statement, which reads in part:
…to educate and train scientists and engineers to pursue technologies related to regenerative medicine and train a generation of clinicians in the implementation of regenerative therapies.
The participation and contributions of commercial attendees along with MIRM faculty and trainees provided for insightful discussions facilitated by a “Speed Dating session” where faculty met with industry participants in a round robin format. This event emphasized another section of the Institute’s mission statement, “…to support the commercialization of technologies…and accelerate the translation of research discoveries to clinical implementation and patient benefit.”
Highlights of the retreat included the McGowan Distinguished Lecture delivered by Irving L. Weissman, MD, of Stanford University, the Virginia & D.K. Ludwig Professor for Clinical Investigation in Cancer Research, a professor of Developmental Biology, Neurosurgery, and Biological Sciences.
The Monday night dinner included presentations by Rebecca Bagley, the Deputy Secretary of the PA Department of Economic and Community Development and Rhode Island Lieutenant Governor, Elizabeth Roberts.
Working sessions at the retreat were hosted by a variety of speakers from multiple disciplines. Key faculty members from Duke University, the University of Michigan, the University of Nebraska Medical Center, the Texas Heart Institute, Georgia Institute of Technology, and the Osaka University Graduate School of Medicine in Japan joined McGowan faculty to explore numerous topics.
The poster session continued to be one of the highlights with presentations from faculty and student researchers. Dr. Kacey Marra and her committee organized the session and judged the posters. Winners of the poster session were:
Category A: Artificial Organs & Medical Devices & Modeling
First Place Winner:
“Development of Hollow Fiber-Based Bioreactor Systems for 3D Neuronal Cell Cultures,” by Candace Brayfield, Kacey Marra, John Leonard, X. Tracy Cui, and Joerg Gerlach
Honorable Mention:
“Cytokine Hemoadsorption Dynamics Using Confocal Laser Scanning Microscopy,” by Jeremy Kimmel and William Federspiel
Category B: Bioengineering and Tissue Engineering
First Place Winner:
“Ventricular Function in Mice Expressing Constitutively Phosphorylated Cardiac Troponin I,” by JA Kirk, C Evans, SH Smith, AF Steward, GA MacGowan, RJ Solaro, and SG Shroff
Honorable Mention:
“Characterization, Isolation, and Multi-Lineage Differentiation of Human Adult Dental Pulp Perivascular Stem Cells,” by Bonnie Teng, Mihaela Crisan, Tea Soon Park, Alison Logar, Pieter Heemstra, Neil Robertson, Bin Sun, Bruno Peault, and Charles Sfeir
Category C: Cellular Therapies
First Place Winner:
“Human Fetal Placenta Blood Vessels on Skeletal Myogenesis,” by Tea Soon Park, Chien-Wen Chen, Alison Logar, and Bruno Peault
Honorable Mention:
“Lymph Nodes as a New Site for Liver Regeneration,” by Toshitaka Hoppo, Rohan Manohar, Donna Beer Stolz, and Eric Lagasse
Thanks are extended to all who made this year’s Retreat a success!
Dr. Stephen Badylak shared his advances in tissue engineering with a national audience last week when his work was highlighted on the CBS Sunday Morning, in a piece called “Medicine's Cutting Edge: Re-Growing Organs--The Future Is Here: Regenerative Powder, Ink Jet Heart Cells And Custom-Made Body Parts.” The segment was hosted by correspondent Wyatt Andrews, who invited viewers to join him on a trip to the “scientific frontier.”
After discussing the extra-cellular matrix powder that regrew the tip of Lee Spievack’s severed finger, the next area featured was cardiovascular research, with University of Pittsburgh and McGowan Institute faculty member Joon Sup Lee, MD, Associate Professor of Medicine and Clinical Director of the Cardiovascular Institute at UPMC Presbyterian. Dr. Lee was shown injecting the adult stem cells of a patient directly into the heart to facilitate vascular regeneration.
“It’s what we consider the Holy Grail of our field for coronary heart disease,” said Dr. Lee. The reason for such a lofty claim is that if stem cells can actually reproduce into arteries, the need for surgery would become less if not altogether nil.
Andrews also addressed Dr. Atala’s work at Wake Forest University; specifically, the lab grown bladders that are now being tested in clinical trials.
Read more and watch the CBS news feature
Alan J. Russell, PhD, was one of a group of McGowan Institute faculty members contributing to the Cornerstones Symposium held at Carnegie Mellon University (CMU) on March 25, 2008. The symposium was sponsored by the Tepper School of Business at CMU along with its Donald H. Jones Center for Entrepreneurship.
The symposium was entitled “Entrepreneurial Pittsburgh: Building Bridges to a City’s New Future.” The focus was on interdisciplinary culture and collaboration, exhibited by the close cooperation between CMU, the University of Pittsburgh, and UPMC for research and other efforts aimed at promoting entrepreneurial vitality. McGowan Institute also hosted a booth with informational brochures as part of the symposium exhibits.
Since Pittsburgh has been recently recognized as the leading U.S. city for growth in venture-funded businesses, one of the goals of the symposium was to connect leading authorities from around the world to share their knowledge and experience.
This year’s event was the seventh annual symposium. Other speakers from Pitt included Dr. Robert Kormos, Dr. Arthur Levine, Dean of the School of Medicine, and Chancellor Mark Nordenberg.
Read more: Tepper School of Business
McGowan Institute faculty member Eric Lagasse, PharmD, PhD, is an associate professor in the University of Pittsburgh Department of Pathology and the Director of the Cancer Stem Cell Center (a collaborative partnership of the McGowan Institute and University of Pittsburgh Cancer Institute). Recently, his paper, “Cancer stem cells with genetic instability: The best vehicle with the best engine for cancer,” made the top ten chart of articles that have been downloaded most frequently from the Gene Therapy website in recent weeks.
Abstract of Dr. Lagasse’s paper:
Our understanding of the role of stem cells in cancer development is evolving quickly. In the course of tumor expansion, a subpopulation of tumor cells with stem cell-like features has been noted. These cancer stem cells give rise to transit amplifying tumor cells, which comprise the majority of the tumor mass prior to terminal differentiation. Combining this finding with genetic instability, a well-known engine for cancer development and metastases, a new model emerges for cancer where normal stem cells and their cellular pathway acquire stochastic malignant abilities. In this model, when cancer stem cells self-renew, many genetic variants are produced. Just as microbes 'learn' to defeat antibiotics, genetically heterogeneous cancer stem cells may possibly acquire resistance to various chemotherapeutic approaches. Drug-resistant microorganisms selected by spontaneous mutation of bacterial DNA may not be so different than the drug-resistant and genetically instable cancer stem cells recurring after chemotherapeutic treatment. In this gloomy view of cancer, cancer stem cells with genetic instability can be considered as 'the best vehicle with the best engine', a formidable challenge for the future development of new anticancer therapies.
Congratulations, Dr. Lagasse!
Read the full text… (Gene Therapy (2008) 15, 136–142)
Tao Cheng, MD, associate professor in the School of Medicine’s biochemistry and molecular genetics program, as well as a McGowan faculty member, has received the Scholar Award from the Leukemia and Lymphoma Society. The Scholar Award carries a significant cash grant to be used for further research: $550,000. According to the Leukemia and Lymphoma Society, the award is give only to highly qualified investigators who have shown a capacity for independent, sustained original investigation in the field of leukemia, lymphoma and myeloma. One of Dr. Cheng’s ongoing research projects is self-renewal mechanisms for normal and leukemia stem cells.
Dr. Cheng first arrived in the United States in 1993 as a Research Fellow in Molecular Biology at Hipple Cancer Research Center in Dayton, Ohio. From 1994-1997, he pursued Postdoctoral Fellowships in Hematology and Oncology at the Deaconess Hospital and Massachusetts General Hospital, both located in Boston, Mass. Following appointments as an assistant in biology at Massachusetts General Hospital and an instructor of Medicine at Harvard Medical School, Dr. Cheng was recruited by the University of Pittsburgh in 2001. Among other awards, Dr. Cheng was also selected for the Innovative Award from the PNC Foundation in 2003.
Flordeliza Villanueva, MD, was recently selected to the Association of University Cardiologists (AUC). Dr. Villanueva is an associate professor of medicine and director of non-invasive cardiac imaging at the UPMC Cardiovascular Institute. She is also a McGowan faculty member and director of the Center for Ultrasound Molecular Imaging and Therapeutics.
Dr. Villanueva joined the University of Pittsburgh faculty in 1992. She was a student in a 6-year BA/MD program at Boston University in Boston, Mass. and received her MD in 1984. Dr. Villanueva completed her internal medicine residency at Duke University in North Carolina. She then received post-doctoral fellowships from the University of Pittsburgh and the University of Virginia in Charlottesville, Va. In 2002, she was the recipient of the Feigenbaum Lectureship and Award, one of the most prestigious awards of the American Society of Echocardiography. It is typically conferred upon a young investigator who has been deemed by the Society to have made major contributions to the field of echocardiography.
Research led by McGowan Institute for Regenerative Medicine faculty member Jay K. Kolls, MD, Chief of the Division of Pediatric Pulmonary Medicine, Allergy, and Immunology at Children’s Hospital of Pittsburgh of UPMC, identified for the first time the importance of a protein known as interleukin 22 (IL-22) in the immune response to a strain of bacterial pneumonia. In the laboratory, the researchers were able to effectively treat mice with pneumonia by using purified IL-22. The identification of this key protein target may be a crucial factor in the development of a vaccine to prevent pneumonia as well as new therapies to treat it. Pneumonia is currently the leading killer of children worldwide.
Pneumonia causes almost one in five deaths in children under age 5 worldwide—more than 2 million children each year, according to the World Health Organization. It kills more children than any other disease—including AIDS and malaria combined.
“Currently there is no vaccine that covers all kinds of pneumonia, and antibiotic treatment is sometimes limited by antibiotic resistance. As acute respiratory infections are the No. 1 killer of children in the world, progress in the development of novel vaccines or new, more effective treatments is critical,” said Dr. Kolls, the Neils K. Jerne Professor of Pediatrics and Immunology at the University of Pittsburgh School of Medicine. “Our results raise the possibility of developing new protein-based therapies using IL-22 to limit or prevent pneumonia.”
Read the Nature Medicine article
The McGowan Institute for Regenerative Medicine faculty member Patrick Kochanek, MD, Director at the Safar Center for Resuscitation Research in Pittsburgh and Vice Chairman at the Department of Critical Care Medicine, University of Pittsburgh, and colleagues at other institutions in North America are studying the molecular secrets of hibernation and extreme hypothermia in hopes of finding a new generation of treatments that can slow down metabolism for just a few hours. Their goal is to buy time after a car accident, gunshot wound, or massive heart attack and get the patient into surgery at a hospital before they die or suffer extensive brain damage.
Their work is in the very preliminary stages, and human trials are only now being planned. But the implications are huge if any of these treatments work. Without oxygen, heart cells begin to die in 20 minutes. Brain cells last just five minutes without oxygen. Despite defibrillators and other modern gear, survival rates after cardiac arrest are around 30% inside hospitals and 5% or so outside of them.
Drs. Kochanek and Samuel A. Tisherman, M.D., hope that much more radical cooling can save trauma victims. In experiments on dogs they have found that by pumping liters of ice-cold salt water into their arteries and cooling them down to 59 degrees they can preserve vital organs up to three hours after the heart stops. In one study, the deep chill saved the lives of 12 of 14 dogs whose hearts were stopped after blood loss; control animals treated with CPR all died.
Read more…Forbes
Recent medical news indicates that the use of drug-coated stents in patients with complex heart disease is associated with a lower rate of repeat procedures without an increased risk of death or heart attacks compared to bare metal stents. This current report is the largest and most detailed analysis comparing the safety and efficacy of drug-coated and bare metal stents for off-label indications, that is, when used for patients with complex disease. McGowan Institute faculty member Joon Sup Lee, MD, Assistant Professor of Medicine at the University of Pittsburgh, Clinical Director of the Cardiovascular Institute at the University of Pittsburgh Medical Center, and Associate Chief in the Division of Cardiology at the University of Pittsburgh School of Medicine, reports along with other study researchers that this study was conducted in response to an FDA call for more data on what has become common practice by cardiologists worldwide—using stents, particularly drug-eluting stents, in high-risk patients with complex conditions.
Even when the stent procedure is successful, the stented area can suffer re-narrowing over time caused by excess scar tissue formation that the body forms in response to the stent. It is accepted knowledge that when these stents are used in higher risk patients, the risk of re-narrowing is greater than when they are used in patients with fewer medical complications. The drug-coated stents, often preferred by cardiologists, reduce the amount of scar tissue formation, resulting in a lower likelihood of artery re-narrowing over time, compared to bare metal stents.
The study’s lead author, Oscar C. Marroquin, MD, Assistant Professor of Medicine, University of Pittsburgh School of Medicine, and Director, Center for Interventional Cardiology Research at the University of Pittsburgh Medical Center’s Cardiovascular Institute.
Read more… (The New England Journal of Medicine, 2008; 358:342-52)
The Regenerative Medicine Podcasts continue to explore pertinent topics. The most recent podcasts are:
#48-Joan Schanck – Ms. Schanck, Director of Education and Workforce Development at the Pittsburgh Tissue Engineering Initiative (PTEI) discusses educational programs for students from K-12 and beyond.
#49-Steve Winowich – Mr. Winowich, Director of Clinical Bioengineering with the Artificial Heart Program at UPMC, reviews the unique partnership between clinical staff and bioengineers in regard to providing mechanical circulatory support to patients prior to a heart transplant.
Visit www.regenerativemedicinetoday.com to keep abreast of the new interviews.
| Authors: | Mahesh P. Gupta, Sadhana Samant, Stephen H. Smith, and Sanjeev G. Shroff |
| Title: | HDAC4 and PCAF bind to cardiac carcomeres and play a role in regulating myofilament contractile activity |
| Summary: | Reversible acetylation of lysine residues within a protein is considered a biologically relevant modification that rivals phosphorylation (Kouzarides, T. (2000) EMBO J. 19, 1176–1179). The enzymes responsible for such protein modification are called histone acetyltransferases (HATs) and deacetylases (HDACs). A role of protein phosphorylation in regulating muscle contraction is well established (Solaro, R. J., Moir, A. J., and Perry, S. V. (1976) Nature 262, 615–617). Here we show that reversible protein acetylation carried out by HATs and HDACs also plays a role in regulating the myofilament contractile activity. We found that a Class II HDAC, HDAC4, and an HAT, PCAF, associate with cardiac myofilaments. Primary cultures of cardiomyocytes as well as mouse heart sections examined by immunohistochemical and electron microscopic analyses revealed that both HDAC4 and PCAF associate with the Z-disc and I- and A-bands of cardiac sacromeres. Increased acetylation of sarcomeric proteins by HDAC inhibition (using class I and II HDAC inhibitors or anti-HDAC4 antibody) enhanced the myofilament calcium sensitivity. We identified the Z-disc-associated protein, MLP, a sensor of cardiac mechanical stretch, as an acetylated target of PCAF and HDAC4. We also show that trichostatin-A, a class I and II HDAC inhibitor, increases myofilament calcium sensitivity of wild-type, but not of MLP knock-out mice, thus demonstrating a role of MLP in acetylation-dependent increased contractile activity of myofilaments. These studies provide the first evidence that HATs and HDACs play a role in regulation of muscle contraction. |
| Source: | The Journal of Biological Chemistry, 283 (15):10135-10146, 2008. |
| PIs: | Eric Lagasse, PhD and Joerg Gerlach (co-investigator) |
| Title: | Ovarian Cancer, Stem Cells and Bioreactors |
| Description: | Addressing the needs of new approaches for anti-cancer therapies by combining stem cell biology, cancer biology and bioengineering. Our central hypothesis is that cancer stem cells are initiating and sustaining the growth of ovarian cancer. In consequence, the identification of the cancer stem cells represents a major step forward in the elucidation of ovarian cancer hierarchy and could hold the key to understanding the origin and maintenance of ovarian cancer, the relapses and possibly the metastases in advanced cases. Another problem facing cancer cell biology is the access of in vitro culture models for research and study of cancer development and its pathophysiology. Here we propose to adopt bioreactors used for bioartificial livers (BAL) to provide tumor cells with a 3-D perfusion culture instrument that recapitulate vasculature and microenvironment. |
| Source: | Department of the Army |
| Term: | 04/01/08-09/30/08 |
| Amount: | $111,375 |
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