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 Water forms 'spine of hydration' around DNA, group finds
26.05.2017 | Cornell University

nachricht How herpesviruses win the footrace against the immune system
26.05.2017 | Helmholtz-Zentrum für Infektionsforschung

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Can the immune system be boosted against Staphylococcus aureus by delivery of messenger RNA?

Staphylococcus aureus is a feared pathogen (MRSA, multi-resistant S. aureus) due to frequent resistances against many antibiotics, especially in hospital infections. Researchers at the Paul-Ehrlich-Institut have identified immunological processes that prevent a successful immune response directed against the pathogenic agent. The delivery of bacterial proteins with RNA adjuvant or messenger RNA (mRNA) into immune cells allows the re-direction of the immune response towards an active defense against S. aureus. This could be of significant importance for the development of an effective vaccine. PLOS Pathogens has published these research results online on 25 May 2017.

Staphylococcus aureus (S. aureus) is a bacterium that colonizes by far more than half of the skin and the mucosa of adults, usually without causing infections....

Im Focus: A quantum walk of photons

Physicists from the University of Würzburg are capable of generating identical looking single light particles at the push of a button. Two new studies now demonstrate the potential this method holds.

The quantum computer has fuelled the imagination of scientists for decades: It is based on fundamentally different phenomena than a conventional computer....

Im Focus: Turmoil in sluggish electrons’ existence

An international team of physicists has monitored the scattering behaviour of electrons in a non-conducting material in real-time. Their insights could be beneficial for radiotherapy.

We can refer to electrons in non-conducting materials as ‘sluggish’. Typically, they remain fixed in a location, deep inside an atomic composite. It is hence...

Im Focus: Wafer-thin Magnetic Materials Developed for Future Quantum Technologies

Two-dimensional magnetic structures are regarded as a promising material for new types of data storage, since the magnetic properties of individual molecular building blocks can be investigated and modified. For the first time, researchers have now produced a wafer-thin ferrimagnet, in which molecules with different magnetic centers arrange themselves on a gold surface to form a checkerboard pattern. Scientists at the Swiss Nanoscience Institute at the University of Basel and the Paul Scherrer Institute published their findings in the journal Nature Communications.

Ferrimagnets are composed of two centers which are magnetized at different strengths and point in opposing directions. Two-dimensional, quasi-flat ferrimagnets...

Im Focus: World's thinnest hologram paves path to new 3-D world

Nano-hologram paves way for integration of 3-D holography into everyday electronics

An Australian-Chinese research team has created the world's thinnest hologram, paving the way towards the integration of 3D holography into everyday...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Marine Conservation: IASS Contributes to UN Ocean Conference in New York on 5-9 June

24.05.2017 | Event News

AWK Aachen Machine Tool Colloquium 2017: Internet of Production for Agile Enterprises

23.05.2017 | Event News

Dortmund MST Conference presents Individualized Healthcare Solutions with micro and nanotechnology

22.05.2017 | Event News

 
Latest News

How herpesviruses win the footrace against the immune system

26.05.2017 | Life Sciences

Water forms 'spine of hydration' around DNA, group finds

26.05.2017 | Life Sciences

First Juno science results supported by University of Leicester's Jupiter 'forecast'

26.05.2017 | Physics and Astronomy

VideoLinks
B2B-VideoLinks
More VideoLinks >>>