McGowan Institute?
November 2008 | VOL. 7, NO. 11 | www.McGowan.pitt.edu
ERC Grant to Focus on Biodegradable Devices
Multiple McGowan Institute faculty members contributed to the successful application that resulted in a partnership between North Carolina Agricultural and Technical State University (NCAT), the University of Pittsburgh, and the University of Cincinnati (UC). The partnership is the recipient of a 5-year, $18.5 million Engineering Research Center (ERC) grant from the National Science Foundation (NSF). The much sought after NSF ERC grant supports large-scale university and industry collaborations on pioneering technologies considered important to future generations.
The NSF Engineering Research Center for Revolutionizing Metallic Biomaterials will focus primarily on producing three technologies:
- Biodegradable and self-adapting devices and smart constructs for craniofacial and orthopedic reconstructive procedures;
- Similarly behaving cardiovascular devices such as stents; and
- Miniaturized sensing systems that monitor and control the safety and effectiveness of biodegradable metals inside the body (a technology that could lead to responsive biosensors that could help doctors determine when and where diseases occur in the body).
Contributing McGowan Institute faculty include:
- Harvey Borovetz, PhD, deputy director of Artificial Organs and Medical Devices, McGowan Institute; chair, Bioengineering Department
- Xinyan Tracy Cui, PhD, assistant professor, Department of Bioengineering
- Prashant Kumta, PhD, Edward R. Weidlein chair, Swanson School of Engineering; professor, Departments of Bioengineering, Chemical and Petroleum Engineering, and Mechanical Engineering and Materials Science
- Kacey Marra, PhD, assistant professor, department of Surgery; director, Plastic Surgery Laboratory; co-director, The Adipose Stem Cell Center, Division of Plastic Surgery
- Charles Sfeir, DDS, PhD, associate professor, Department of Oral Medicine and Pathology
- William Wagner, PhD, McGowan Institute deputy director; professor of Surgery, Bioengineering, and Chemical Engineering; director of Thrombosis Research for the Artificial Heart and Lung Program; deputy director, ERC
- Savio Woo, PhD, DSc, University Professor, Bioengineering Department; founder and director of the Musculoskeletal Research Center.
As part of this research effort, dozens of engineers and doctors from universities and industries around the world will collaborate on the project announced September 4, 2008, to develop implantable devices made from biodegradable metals. The devices will be designed to adapt to physical changes in a patient’s body and dissolve once they have healed. Naturally dissolving plates, screws, stents, and other devices will reduce the need for follow-up surgeries as well as the potential for complications from these major orthopedic, craniofacial, and cardiovascular procedures. The end result is a savings of millions of dollars worldwide in patient medical expenses, not to mention the added pain and inconvenience attributed to these follow-up surgeries.
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McGowan Institute for Regenerative Medicine faculty member Andrew Schwartz, PhD, is a Professor of Neurobiology at the University of Pittsburgh. Recently, Scott Pelley of the CBS News Show 60 Minutes visited Dr. Schwartz’s lab to talk about his astounding technology that his team is developing, which directly connects the human brain to a computer. As Mr. Pelley reports, it's like a sudden leap in human evolution - a leap that could one day help paralyzed people to walk again and amputees to move bionic limbs. The connection has already been made for a few people, and for them it has been life changing.
As a systems neurophysiology lab, Dr. Schwartz and his team are interested in the way neural activity drives behavior. Since behavior is generated by neural activity there is a temporal correspondence between them. Their goal is to describe this time-varying relation and to discover fundamental organization principles linking neural activity to behavior.
The research program is centered on the relation between cerebral cortical activity and arm movement. Over the last 20 years, the researchers have found that there is a very good representation of the arm’s trajectory in the collective firing pattern of frontal cortical activity. This representation is robust, predictive, and contains many of the behavioral invariants characteristic of natural arm movement.
In his lab, Dr. Schwartz has implanted a grid of electrodes inside the brains of monkeys. The grid is tiny, but there are 100 sensors, each listening to a different brain cell, or neuron. Dr. Schwartz has been decoding that language by watching the monkey's movement and recording the corresponding signals in its brain.
Asked what that tells him, Dr. Schwartz says, "So there's a relationship between how fast the neuron fires and the way the animal moves its hand. And we're trying to understand that relationship so that if we see a neuron firing we can say, 'Ah, the animal's about to make this kind of movement.'"
Once Dr. Schwartz started to figure out that relationship, he was able to connect the monkey's brain directly to a robotic arm. Within days, the monkey operated the arm as if it was his own. "The monkey has both arms restrained. And we’re recording brain signals from its brain and it’s using those brain signals to operate this entire arm," Schwartz explains. "As well as the gripper."
Dr. Schwartz says the monkey is operating the robotic arm with nothing but his thoughts. Asked what the chances are that a human would be able to do the same thing, he says, "Oh, we think a human being could do much better."
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The 8th Annual McGowan Institute for Regenerative Medicine Scientific Retreat is set to take place on March 9-11, 2009 at Nemacolin Woodlands Resort. An informal mixer will occur on the evening of March 8, 2009. Under the leadership of Dr. William Wagner, the program committee is planning an exciting group of speakers and topics. The program will include distinguished guest speakers, a poster session, and potential external partners and collaborators, so there will be multiple opportunities for networking and collaboration. The registration deadline is February 15, 2009 (or sooner; no reservations will be accepted once the reservation quota is filled.)
Read more and register…
It was in a Chicago bakery that McGowan Institute faculty member Ernest Manders, MD, Professor of Surgery, University of Pittsburgh, first saw Sarah Mues. Dr. Manders was in Chicago for the annual conference for the American Association of Tissue Banks. Sarah and her sister were in the Windy City on vacation and eating lunch. Dr. Manders just had to interrupt and introduce himself.
“We noticed Sarah didn’t have any arms or hands,” Dr. Manders said, recalling the bakery encounter during a telephone interview. “...We saw her pick up a fork and feed herself a salad. I do hand surgery, and I’ve never seen anybody do this in my life.”
During their conversation, Dr. Manders explained to Sarah that a team of doctors in Pittsburgh perform arm and hand transplants, and two of them were at the conference — McGowan Institute faculty members Stefan Schneeberger, MD, and Vijay Gorantla, MD, PhD. Together with their colleague, Andrew Lee, MD, they are a few of the pioneers in this field. Impressed by Ms. Mues’ ability to complete the mundane — to eat a salad, for example — Dr. Manders invited her to the conference.
If the blood tests show Sarah is a potential transplant candidate, she will move on to another round of intensive tests: CAT scans, bone marrow tests, and psychological exams, among others. One test will check her brain’s ability to move her hands. Medical staff will need to check if her brain still remembers how, for example, to wiggle a finger. If all the tests go well, Ms. Mues will have to move to Pittsburgh and wait until a suitable donor could become available at any time, so that she can receive hand transplants.
Based on groundbreaking research and experience in solid-organ transplants, the University of Pittsburgh Medical Center (UPMC) is beginning a novel clinical study on human hand transplantation that seeks to reduce the use of immunosuppressive drugs and their damaging side effects for patients.
Although surgeons from around the world have performed hand transplants successfully for almost 10 years, they have used multiple immunosuppressive medications to prevent rejection of the grafts, increasing the risk of diabetes, hypertension, and other disorders.
In contrast, researchers and surgeons at UPMC propose to implement an immunomodulatory approach known as the “Pittsburgh Protocol,” which entails antibody therapy, donor bone marrow cell infusion, and treatment with a single immunosuppressive drug to reduce toxicity for patients.
“We will be offering another, potentially safer alternative for those who have lost a hand,” said Dr. Lee. “With our focus on reducing the need for multiple immunosuppressant drugs typical of this procedure, we believe that we can restore what many amputees have lost without the risk of devastating side effects.”
Surgeons at UPMC will adapt a two-phase protocol that involves initial antibody treatment followed by bone marrow cell therapy. The goal is not merely to suppress the immune system but to change the way it functions. Transplant patients will receive antibodies to help overcome the initial overwhelming immune response. That will be followed by a bone marrow infusion. The bone marrow cells target specific cells that could reject the hand and help “re-educate” the immune system into thinking that the transplanted hand is not a foreign object. Patients will be treated with tacrolimus, a drug that was first used in liver transplants by Thomas Starzl, M.D., Ph.D. over two decades ago, to maintain the low-grade immunosuppression needed to prevent long-term graft rejection.
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McGowan Institute for Regenerative Medicine faculty member Blair Jobe, MD, FACS, is a member of the medical team treating people with severe, chronic heartburn that does not respond to medication. These patients now have a new surgical treatment option at UPMC that does not require any incisions.
Heartburn, which also is known as acid reflux disease, is a condition in which acid from the stomach creeps up into the esophagus and causes a burning sensation in the chest. According to medical literature, as many as 14 million Americans live with acid reflux disease and complications can lead to esophageal cancer. For patients who do not respond to medication therapy, their only option is surgery. Traditional surgery includes a large open abdominal incision—an operation that takes several hours—and patients must remain in the hospital for a few days.
The FDA-approved device, known as EsophX, is a tubular device that rides over a standard endoscope. With the patient sedated under general anesthesia, the device is inserted into the patient’s mouth down the esophagus and into the stomach. EsophX has both an operating and procedural end, enabling surgeons to view the procedure from a tiny fiber optic camera mounted inside the device. Once the stomach is inflated for surgery, tiny instruments can be deployed to grasp the stomach tissue to begin reconstruction of the valve. The surgeons repeat the procedure until they are satisfied that a one-way valve from the stomach to the esophagus is secured to prevent the backflow of stomach acids.
“Many patients with severe heartburn must take expensive medications, which only treat the symptoms and do not adequately address the underlying problem caused by defective anatomy. With this novel device, we are now able to permanently correct the patient’s anatomy by creating a tissue barrier against stomach fluid moving into the esophagus,” said Dr. Jobe, associate professor of surgery, division of thoracic and foregut surgery, University of Pittsburgh School of Medicine, and director of esophageal research, member of the first team to perform incisionless heartburn surgery in the United States.
“This is an approximately one-hour procedure with a one-night hospital stay, which translates to shorter recovery time and fewer complications for the patient,” he added.
Dr. Jobe and colleagues published a landmark study in a recent issue of Annals of Surgery, proving the anatomic basis for esophageal reconstruction and successfully demonstrating that this technique can be used safely and effectively by securing the tissue that lies between the stomach and esophagus.
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McGowan Institute for Regenerative Medicine affiliate member David Baer, PhD, Director of Surgical Research, U.S. Army Medical Research and Materiel Command's Institute of Surgical Research (ISR), Ft. Sam Houston, TX, and his colleagues there in the last few years have looked into about two dozen hemostatic dressings for use on the battlefield. The Pentagon medical officials announced recently that two new first-aid products are being sent into the combat theater and they could save more service members' lives.
Test results from the ISR showed Combat Gauze field bandages and WoundStat granules both demonstrated marked improvements over what's currently used in the field, Army Col. (Dr.) Paul Cordts of the Army surgeon general's office said.
Excessive blood loss is the No. 1 killer on the battleground, Dr. Cordts, a surgeon, said. Both products can stop bleeding quickly in wounds where tourniquets can't be used, he said. Combat Gauze uses kaolin, a fine, white clay, to stop bleeding, he said, and WoundStat granules react with blood to form a barrier, preventing more bleeding.
More than 92 percent of troops wounded in Iraq and Afghanistan survive their injuries in combat, the highest percentage of any war, according to U.S. Army Medical Department officials. Army Master Sgt. Horace Tyson, a combat medic, said he attributes the high number of people being saved to the advanced tools medics have, such as dressings that stop or slow blood flow from wounds.
Although the new hemostatic dressings are promising great improvements, Dr. Baer said it doesn't mean officials aren't still looking for the next line of products that could offer even more improvements. ISR scientists will continue their efforts for even more cutting-edge products to save lives, he said.
The new dressings are expected not only to save more lives, but also to bring significant cost savings to the government, Dr. Cordts said. Combat Gauze is less than $30 per dressing, compared to the currently used HemCon bandage, which uses chitosan from shrimp shells to stop blood and costs $88 per bandage. WoundStat also is less expensive than the QuikClot granules it replaces.
McGowan Institute for Regenerative Medicine congratulates its faculty members—Marco Zenati, MD (pictured top), Patrick Kochanek, MD (middle), and Dennis McNamara, MD (bottom)—for their 2008 research technology transfer efforts. As reported by the University Times, three start-up companies based on innovations developed at Pitt were created in fiscal year 2008, bringing the total number of start-ups to 69 since Pitt’s Office of Technology Management (OTM) opened in 1996.
The start-ups created in 2008 all were based in the health sciences. They are:
- Cardiorobotics, Inc., which is developing robotic probes for use in minimally invasive cardiac and other surgeries. Marco Zenati, professor of surgery, is a company co-founder and chairs its scientific advisory board.
- EPR-Technologies, Inc., which uses new emergency hypothermia procedures to put trauma victims into temporary suspended animation until treatment can be obtained. The process and equipment were developed by Patrick Kochanek, Xianren Wu and William Stezoski, all of the Department of Critical Care Medicine, and Samuel Tisherman of the Department of Surgery.
- Prevencio, LLC, which was formed to utilize discoveries by William LaFramboise of the Department of Pathology and Oscar Marroquin, Dennis McNamara, and Suresh Mulukutla of the Department of Medicine. The researchers developed a series of protein signatures detectable in body fluids that can reveal signs of vascular disease.
Marc Malandro, associate vice chancellor for Technology Management and Commercialization, stated that OTM is “excited to see a growing number of innovators participating in this process, suggesting that technology commercialization continues to play a growing role as part of the University’s overall goal to see products developed from its research benefit society.”
McGowan Institute for Regenerative Medicine, along with the University of Pittsburgh School of Engineering, congratulates the recipient of the 2007-2008 Board of Visitor’s (BOV’s) Faculty Award: Anna Balazs, PhD, McGowan Institute faculty member and University of Pittsburgh Distinguished Professor of Chemical Engineering and Robert Luft Professor of Engineering. The purpose of the BOV’s Faculty Award is to recognize the single-most outstanding member of the School of Engineering faculty who has had the most productive previous academic year in areas such as program development, leadership in the development of graduate research programs, meritorious recognition by peers at the national level, and special recognition as a teacher.
Professor Balazs’ work has focused on developing theoretical and computational models to capture the behavior of polymer blends, nanocomposites, complex fluids, and colloidal systems. She helps create materials “by design” by developing predictive models for the behavior of these advanced materials. It is in this area that Dr. Balazs and her research group have made fundamentally important and unique contributions, which are allowing scientists to understand how choices made at the molecular level affect the macroscopic performance of the system. Dr. Balazs’ work is having a significant impact because she attacks complex yet realistic systems – systems that are usually considered too heterogeneous to be modeled by anything but empirical approaches. Her work is both theoretically elegant and applicable to real materials of industrial relevance.
Congratulations, Dr. Balazs!
In the November 2008 issue of Orthopedics Today, McGowan Institute for Regenerative Medicine faculty member Constance Chu, MD, the Albert B. Ferguson Jr., MD, Endowed Chair in Orthopaedic Surgery, responded to questions from Douglas Jackson, MD, Chief Medical Editor of the publication, about the effects of local intra-articular anesthesia injections on cartilage. Most orthopaedic surgeons routinely use intra-articular injections f anesthesia in their office practices and following arthroscopic procedures. There is little information available on the potential chondrotoxicity and long-term sequelae of these injections. After reading some of Dr. Chu’s research, Dr. Jackson felt it beneficial for her to share some of her laboratory findings and insight into this subject.
Dr. Chu has studied the effects of commonly used agents for intra-articular injections to include lidocaine, bupivacaine, and the combined effects of lidocaine and Depo-Medrol (methylprednisolone acetate, Pfizer) on articular chondrocytes in vitro. In her research she has found dose- and time-dependent toxic effects of all these agents on articular chondrocytes.
Dr. Chu spoke of her in vitro study examining the viability of human and bovine articular chondrocytes and osteochondral tissues following exposure to bupivacaine. In the study, toxicity was defined by using flow cytometry, time-lapse confocal microscopy, and three-dimensional volumetric imaging to count fluorescently stained live and dead cells at varying time points after exposure to different concentrations of bupivacaine for durations ranging from 15 to 60 minutes.
Several models of exposure were used: intermittent exposure, continuous exposure, and in situ exposure within cartilage with and without intact articular surfaces. Chondrocyte viability following defined exposure was measured using flow cytometry. Time-lapse confocal microscopy was used to quantify chondrocyte death during continuous exposure. Three-dimensional volumetric imaging was used for in situ assessment of chondrocyte viability within articular cartilage after bupivacaine exposure.
Chondrocyte death can be observed in the laboratory within minutes after exposing articular cartilage to a toxic agent by using appropriate dyes and fluorescent microscopy. Dr. Chu and her team are currently analyzing data from an in vivo study following single injection of potentially chondrotoxic agents.
The McGowan Institute Distinguished Lecture Series will welcome Jeffrey A. Hubbell, PhD on March 9, 2009 at the McGowan Institute Scientific Retreat. Dr. Hubbell is a full Professor of Biomedical Engineering and director of the Institute for Biomedical Engineering of the Ecole Polytechnique Fédérale de Lausanne and the University of Zurich, Professor of Materials Science and of Material Science, and a University professor at the Medical Faculty.
The McGowan Institute will welcome Marie E. Csete, MD, PhD on April 9, 2009. Dr. Csete is the Chief Scientific Officer at the California Institute for Regenerative Medicine. Her topic will be “Roadblocks to translation of hES cell-derived therapies.” A reception and Molecular Art Exhibit will follow. The featured artist will be the Center for Biological Imaging.
The previous Distinguished Lecture was delivered on October 23, 2008 by Arnold I. Caplan, PhD, Professor of Biological Science, Director of the Skeletal Research Center at Case Western Reserve University. His topic was “Adult Mesenchymal Stem Cells: New Cell-based Therapies for Regenerative Medicine”
The University of Pittsburgh Office of the Provost, Office of Technology Management, and Office of Enterprise Development, Health Services held their 4th Annual Celebration of Innovation on October 6, 2008. The award honors those whose innovations have successfully been transformed into licensing agreements and start-up companies. Among the recipients were several McGowan Institute members. Congratulations to the following faculty, students, and graduates:
Stephen Badylak |
Michael Lotze Daniel McKeel Dennis McNamara David Schwartzman Kimimasa Tobita William Wagner Alan Wells Marco Zenati |
A Glimmer of Hope Foundation has launched a new fundraiser called “Candy for the Cure,” which is an effort designed to raise money for specific projects related to breast cancer research. The sale of each one pound box of assorted chocolates will provide funding for a new microscope for the Hillman Cancer Center. Also available are Steeler Gift Baskets, which include Steeler ornaments and other memorabilia. McGowan Institute member Dr. Vera Donnenberg of the Hillman Cancer Center urges all to consider purchasing these items. She said, “If you have not yet bought your Christmas presents, would you please consider chocolates and Steeler ornaments? We need to reach as many chocolate-loving Steeler fans as we can!”
Funds from A Glimmer of Hope support breast cancer research in premenopasal women. In 2004, close to a quarter million women were diagnosed with breast cancer in the United States, making it the most common malignancy in women. Not just a disease of older women, approximately 15% of new cases of breast cancer occur annually in women of reproductive age. There are many questions left unanswered in the treatment of breast cancer in younger women. Given the fact that tens of thousands of women of reproductive age are diagnosed with breast cancer each year and that women are increasingly postponing childbearing, it is the foundation’s mission to fund those seeking answers to these questions. The foundation advocates that raising the awareness of younger women and physicians about breast cancer in younger women should be a national priority.
For more information and to purchase candy or gift baskets, please visit the Glimmer of Hope website at http://www.symbolofthecure.com/index.
McGowan Institute for Regenerative Medicine faculty member Tao Cheng, MD, Associate Professor in Radiation Oncology at the University of Pittsburgh and Co-Leader of the Cancer Stem Cell Program at the University of Pittsburgh Cancer Institute, was 1 of 10 researchers nationwide to receive recently a National Institute of Allergy and Infectious Diseases (NIAID) investigator-initiated grant focused on improving the diagnosis and treatment of individuals exposed to radiation. This 5-year award is estimated to be up to $4 million for the first year.
The NIAID, part of the National Institutes of Health, has awarded these latest grants to develop new and better diagnostics and treatments for radiation exposure after a nuclear attack. In the event of a nuclear attack, people exposed to radiation would suffer from injuries to important tissues and organs, such as the skin, lungs, blood cells, nervous system, and digestive tract. The severity of these injuries would vary. Proper diagnosis and prompt treatment of those affected is a key issue.
“These…new awards will help seed basic science research in areas of radiation exposure after nuclear attack that are not currently being addressed,” says Richard Hatchett, M.D., associate director of Radiation Countermeasures Research and Emergency Preparedness at NIAID.
McGowan Institute for Regenerative Medicine faculty member Partha Roy, PhD, Assistant Professor of Bioengineering and Pathology at the University of Pittsburgh, is a member of the international team of researchers who, through the University of New England (UNE), Armidale, New South Wales, Australia, has won a $252,000 grant from the National Health and Medical Research Council for an investigation of a protein that suppresses the growth of cancers. The project, titled “Profilin: A novel target for cancer therapy,” includes the research efforts of Dr. Roy and scientists based in the United States, Denmark, and Australia.
The broad research interest of Dr. Roy's lab is to study the molecular mechanisms of cell migration. More specifically, the lab is investigating the role of profiling – an important actin-binding protein – in cell migration, using breast cancer as model system. Ongoing studies focus on how molecular perturbations of profilin can be utilized to suppress invasive and metastatic potential of breast cancer cells. The laboratory is also investigating how profilin's interaction with other cellular proteins are regulated in vivo and what role they play during cell migration. These projects involve a combination of molecular biology, cell biology, biochemical, and microscopic imaging techniques. Dr. Roy will support the UNE project’s research team as an expert in controlling the expression of profilin within living cells.
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McGowan Institute for Regenerative Medicine faculty member Louis D. Falo Jr., M.D., Ph.D. (pictured top), Professor and Chairman of the Pitt Department of Dermatology, and his team, which includes McGowan Institute faculty member Theresa Whiteside, Ph.D. (pictured bottom), Director of the Immunologic Monitoring and Cellular Products Laboratory at the University of Pittsburgh Cancer Institute, received a $1 million research grant from Project BioShield (funded by the National Institutes of Health, National Institute of Allergy and Infectious Diseases, and the Department of Health and Human Services) to develop a topical way to administer a radiation mitigator drug quickly and easily to a large patient population. The GS-nitroxide drug JP4-039, identified by the Pitt research team in 2004 as a radioprotector, could counter the effects of radiation exposure in case of large-scale public exposure.
A team of researchers led by Joel Greenberger, M.D., professor and chairman of the Department of Radiation Oncology at the University of Pittsburgh School of Medicine, will develop the GS- nitroxide drug JP4-039. Using both mouse model and human cell and tissue research, they have shown that the drug, when delivered 24 hours after irradiation, enhances cell recovery. According to Dr. Greenberger, JP4-039 can be delivered directly to the mitochondria, the energy-producing areas of all cells. When this occurs, the drug assists the mitochondria in combating irradiation-induced cell death.
The Regenerative Medicine Podcasts continue to gain listeners and explore pertinent topics. Remember to tune in and keep abreast of new interviews. The most recent podcasts are:
#58 – John Manzetti, MBA – Mr. Manzetti is the President and Chief Executive Officer of Pittsburgh Life Sciences Greenhouse (PLSG). He overviews the focus and achievements of the PLSG. Mr. Manzetti earned his Bachelor’s degree in Business Administration from Geneva College and his MBA from the University of Akron.
#59 – Vera Donnenberg, PhD – Dr. Donnenberg is an Assistant Professor of Surgery and Pharmaceutical Science at the University of Pittsburgh. Her lab is focused on approaches that can be translated into the biologic basis for treatment failure and identifying new immunological therapeutic targets. She introduces the concept of a cancer vaccine to address these needs.
Visit www.regenerativemedicinetoday.com to keep abreast of the new interviews.
| Authors: | Gharaibeh, B., A. Lu, J. Tebbets, B. Zheng, J. Feduska, M. Crisan, B. Péault, J. Cummins, and J. Huard. |
| Title: | Isolation of a slowly adhering cell fraction containing stem cells from murine skeletal muscle by the preplate technique |
| Summary: | This is an excellent documentation of all details and nuances of the preplate technique that answer questions regarding the preplate technique procedure that Gharaibeh and his colleagues are asked by specialists and others in the fields of skeletal muscle and adult stem cell biology. The authors Gharaibeh, Péault, Huard and other colleagues at the Stem Cell Research Center details a history of the technique with a long list of authors that have adopted the technique to isolate MDSC even if they were named different and compared different modifications to the technique made by different authorities. Furthermore, the article contains a thorough methods and materials section which is hyperlinked to the web sites of different vendors. It also contains a trouble shooting guide and excellent illustrations that explain the process. |
| Source: | Nature Protocols. 3:1501-1509. |
PI |
Edward V. Prochownik |
Co-Investigators |
Eric Lagasse, William Saunders, and Youjun Li |
Title |
Function of a Glycoprotein Ibα, a Subunit of the Von Willebrand’s Factor Receptor as a Transforming Oncoprotein |
Description |
De-regulation of the CMYC gene and/or its encoded protein, c-Myc, are among the most common molecular abnormalities in human cancers. c-Myc is a particularly notorious oncoprotein because, in addition to being acutely transforming, it can also mediate genomic instability (GI) at several levels, which contributes to ongoing mutational changes and tumor cell evolution. A major focus of our laboratory has been the identification of transcriptional targets for c-Myc, which normally functions as a general transcription factor. Many c-Myc targets have been identified but only a small number have been shown actually to recapitulate the transforming properties of c-Myc itself. Recently, we have identified a totally unexpected down-stream target of c-Myc, GPIBα, whose encoded proteinGpIbα functions as a subunit of the von Willebrand’s factor receptor (VWFR), previously believed to be expressed only on platelets and megakaryocytes. In its traditional role, VWFR interacts with von Willebrand’s factor expressed by the vascular sub-endothelium and thus serves to immobilize platelets and allow their aggregation and activation during the initial stages of blood clot formation. Unexpectedly, we have found that GpIbα is necessary for c-Myc to promote GI and, by itself, is sufficient both for transformation and GI. In a large panel of normal and tumor cell lines, we have found that GpIbα is expressed at highest levels in the latter cells and in direct proportion to c-Myc. Now, in collaboration with Dr. Eric Lagasse (McGowan Institute for Regenerative Medicine) and Dr. William Saunders (University of Pittsburgh Department of Biological Sciences), we propose to explore further the mechanism(s) by which GpIbα promotes GI and cellular transformation and to delineate GpIbα’s role in in vivo tumorigenesis. Thus, in Specific Aim 1, we will define the mechanisms by which GpIbα over-expression leads to GI and transformation (Prochownik). In Specific Aim 2, we will assess the role of GpIbα in promoting tumorigenesis of established cancer cell lines (Prochownik). In Specific Aim 3, we will develop an in vivo model of GpIbα-mediated GI and transformation (Lagasse). Finally, in Specific Aim 4, we will evaluate in detail the nature of GpIbα-mediated GI (Saunders). Together, these studies will provide new insights into a previously unrecognized and unexpected oncoprotein, namely GpIbα, and will define the mechanisms by which this newly described function differs so dramatically from its traditional role in megakaryocytes and platelets. |
Source |
Children’s Hospital of Pittsburgh |
Term |
7/1/08-6/30/09 |
| Amount: | $62,575 |
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