Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

UCSD researchers create roadmap to integrin activation

19.09.2006
Calling it an important technical advance in the study of the complex receptors and pathways of the body's cellular system, researchers at the University of California, San Diego (UCSD) School of Medicine have reconstructed the signaling pathways that impact activation of a receptor that is critical to the control of bleeding and to the thrombosis that occurs in heart attacks and strokes.

Their work to take apart and re-build the signaling pathway that regulates activation of the body's most abundant platelet receptor, an integrin called glycoprotein (GP) IIb-IIIa, provides a powerful and flexible tool for studying therapeutic targets along the pathway that impacts the activation process. This activation leads to changes in the cells' surface receptors – changes that enable platelets to bind to the wall of blood vessels and to one another.

"The road map of the activation pathway could lead to the development of new antithrombotic drugs or treatments for inflammatory diseases. In addition, the ability to engineer these activation pathways may contribute to efforts to develop artificial platelets or leukocytes that could be used in patients with suppressed bone marrow function, for example," said Mark H. Ginsberg, M.D., professor of Medicine at the UCSD School of Medicine. The study will be published on line in Current Biology on September 19.

Integrins are a large family of adhesion molecules that promote stable interactions between cells and their environment. The integrins also act as cellular sensor and signaling molecules, transferring information between the inside and outside of a cell at plasma membrane sites.

Platelets stop the body's bleeding by sticking to one another. When a patient experiences a heart attack or stroke, the platelets stick inappropriately, clumping together and blocking the blood vessel. A signal from inside the platelet to the outside tells the GPIIb-IIIa integrin on the cell's surface to get sticky.

Direct inhibitors of GPIIb-IIIa binding include antithrombotics such as eptifibatide (Integrelin), abciximab (Reopro), and tirofiban (Aggrestat), drugs that reduce thrombosis, or formation of blood clots, by binding to the receptors and completely blocking their function. However, long-term administration of similar drugs doesn't work, in part because of the risk of serious bleeding complications in chronic use.

In sharp contrast, drugs such as clopidogrel (Plavix) and aspirin are two examples of antithrombotics that work well in chronic administration and are widely used for this purpose.

"Drugs such as aspirin and clopidogrel work in large part by blocking the activation of GPIIb-IIIa. These drugs don't work directly on GPIIb-IIIa, but do block signaling pathways that indirectly contribute to GPIIb-IIIa activation. Thus, they achieve a chronic anti-thrombotic effect with acceptable risk of bleeding ," said Ginsberg. He and his colleagues asked themselves if there was another way to block the receptors, by working at the step of activation when the receptors change from non-sticky to sticky – in other words, by blocking the ability of GPIIb-IIIa to activate.

"Up until now, scientists have had a limited understanding of the pathways leading to platelet integrin activation, though we have developed a long list of what might impact the activation process," said Ginsberg. When cultured cells were engineered to express GPIIb-IIIa, agents that usually activated the platelet integrin failed to do so. The UCSD researchers realized that there was something missing, something special about platelets that impacted the activation process.

In 2003, Ginsberg, and Sanford Shattil, M.D., UCSD professor of medicine and Chief of Hematology/Oncology, and colleagues published a paper in the journal Science about the discovery that talin – a large cytoplasmic protein that binds to the inside of an integrin or family of integrins – delivers the critical activation signal. Talin is very important in the linkage between a cell's cytoskeleton and integrins, linkages that cells use to migrate, for example. They noticed that platelets a have much higher concentration of talin that most other cells in the body.

"Talin binding seems to be what throws the activation switch," Ginsberg said. "By adding controllable amounts of talin and the enzyme protein kinase C – an enzyme that modifies other proteins – we found we can get the cell to respond to certain agents that, in turn, activate platelet integrin GPIIb-IIIa."

Using a synthetic approach, the scientists engineered an integrin-activated pathway. By adding protein kinase C, talin or mutants to manipulate the system, they hope to define and map sites where known drugs work, and discover targets along the pathway for new drugs.

"If you think of these pathways as interstate highways on a map, this study now enables us to see other back roads that lead to the destination," said Ginsberg.

Talin is also critical for activation of related integrins, such as those on white blood cells. In these cells, activation of integrins is a critical step in the sticking and migration of white blood cells required for inflammation in diseases such as rheumatoid arthritis and inflammatory bowel disease.

Debra Kain | EurekAlert!
Further information:
http://www.ucsd.edu

Further reports about: GPIIb-IIIa Ginsberg Integrin UCSD antithrombotic bleeding platelet receptor talin

More articles from Life Sciences:

nachricht Nanoparticle Exposure Can Awaken Dormant Viruses in the Lungs
16.01.2017 | Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt

nachricht Cholera bacteria infect more effectively with a simple twist of shape
13.01.2017 | Princeton University

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Designing Architecture with Solar Building Envelopes

Among the general public, solar thermal energy is currently associated with dark blue, rectangular collectors on building roofs. Technologies are needed for aesthetically high quality architecture which offer the architect more room for manoeuvre when it comes to low- and plus-energy buildings. With the “ArKol” project, researchers at Fraunhofer ISE together with partners are currently developing two façade collectors for solar thermal energy generation, which permit a high degree of design flexibility: a strip collector for opaque façade sections and a solar thermal blind for transparent sections. The current state of the two developments will be presented at the BAU 2017 trade fair.

As part of the “ArKol – development of architecturally highly integrated façade collectors with heat pipes” project, Fraunhofer ISE together with its partners...

Im Focus: How to inflate a hardened concrete shell with a weight of 80 t

At TU Wien, an alternative for resource intensive formwork for the construction of concrete domes was developed. It is now used in a test dome for the Austrian Federal Railways Infrastructure (ÖBB Infrastruktur).

Concrete shells are efficient structures, but not very resource efficient. The formwork for the construction of concrete domes alone requires a high amount of...

Im Focus: Bacterial Pac Man molecule snaps at sugar

Many pathogens use certain sugar compounds from their host to help conceal themselves against the immune system. Scientists at the University of Bonn have now, in cooperation with researchers at the University of York in the United Kingdom, analyzed the dynamics of a bacterial molecule that is involved in this process. They demonstrate that the protein grabs onto the sugar molecule with a Pac Man-like chewing motion and holds it until it can be used. Their results could help design therapeutics that could make the protein poorer at grabbing and holding and hence compromise the pathogen in the host. The study has now been published in “Biophysical Journal”.

The cells of the mouth, nose and intestinal mucosa produce large quantities of a chemical called sialic acid. Many bacteria possess a special transport system...

Im Focus: Newly proposed reference datasets improve weather satellite data quality

UMD, NOAA collaboration demonstrates suitability of in-orbit datasets for weather satellite calibration

"Traffic and weather, together on the hour!" blasts your local radio station, while your smartphone knows the weather halfway across the world. A network of...

Im Focus: Repairing defects in fiber-reinforced plastics more efficiently

Fiber-reinforced plastics (FRP) are frequently used in the aeronautic and automobile industry. However, the repair of workpieces made of these composite materials is often less profitable than exchanging the part. In order to increase the lifetime of FRP parts and to make them more eco-efficient, the Laser Zentrum Hannover e.V. (LZH) and the Apodius GmbH want to combine a new measuring device for fiber layer orientation with an innovative laser-based repair process.

Defects in FRP pieces may be production or operation-related. Whether or not repair is cost-effective depends on the geometry of the defective area, the tools...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

12V, 48V, high-voltage – trends in E/E automotive architecture

10.01.2017 | Event News

2nd Conference on Non-Textual Information on 10 and 11 May 2017 in Hannover

09.01.2017 | Event News

Nothing will happen without batteries making it happen!

05.01.2017 | Event News

 
Latest News

Multiregional brain on a chip

16.01.2017 | Power and Electrical Engineering

New technology enables 5-D imaging in live animals, humans

16.01.2017 | Information Technology

Researchers develop environmentally friendly soy air filter

16.01.2017 | Power and Electrical Engineering

VideoLinks
B2B-VideoLinks
More VideoLinks >>>