Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Penn researchers show that protein unfolding is key for understanding blood clot mechanics

10.08.2009
Implications for cardiovascular medicine as well as polymer and materials science

Fibrin, the chief ingredient of blood clots, is a remarkably versatile polymer. On one hand, it forms a network of fibers -- a blood clot -- that stems the loss of blood at an injury site while remaining pliable and flexible.

On the other hand, fibrin provides a scaffold for thrombi, clots that block blood vessels and cause tissue damage, leading to myocardial infarction, ischemic stroke, and other cardiovascular diseases. How does fibrin manage to be so strong and yet so extensible under the stresses of healing and blood flow?

The answer is a process known as protein unfolding, report Penn researchers in Science this week. An interdisciplinary team, composed of investigators from the University of Pennsylvania School of Medicine, the School of Arts and Sciences, and the School of Engineering and Applied Science, has revealed how protein unfolding allows fibrin to maintain its remarkable and contradictory characteristics. Understanding blood clot mechanics could help in the design of new treatments not only to prevent or remove clots that cause heart attacks and strokes but also to enhance blood clotting in people with bleeding disorders. Fibrin's unusual characteristics may also lead to applications in designing new synthetic materials based on its biology.

Building on previous work examining the properties of fibrin, senior author John Weisel, PhD, Professor of Cell and Developmental Biology, and his collaborators studied the mechanics of fibrin clots under stress from the macroscopic scale down to the molecular level. The results were achieved by joint efforts of scientists with different skills, knowledge, and backgrounds: A graduate student Andre E. X. Brown and his adviser Professor Dennis E. Discher brought physics and biomedical engineering; Senior Investigator Rustem I. Litvinov provided his expertise in protein chemistry and medicine; and Prashant K. Purohit, an Assistant Professor of Mechanical Engineering, joined the team to perform theoretical analyses of the experimental data and construct mathematical models of what was happening.

The researchers found that individual fibers in a fibrin blood clot are normally randomly oriented in an intricate meshwork pattern. But when the clot is stretched, the fibers begin to align with each other in the direction of the stress. As the strain continues, the clot stretches and gets longer -- but its volume actually decreases, which surprised the scientists. "That's very unusual," notes Weisel. "It's a property that's been found in a few other materials but it's very rare."

This was a sure sign that something unexpected was going on. "Slipping past each other between or within fibers was not a possibility that could give rise to such high unusual extensions because these fibers were cross-linked. This research provides evidence, both in terms of the mathematical model and with x-ray scattering data, that there is indeed unfolding going on," Purohit says."

The team used a variety of techniques from simple controlled stretching to electron microscopy, X-ray diffraction, atomic force microscopy, and mathematical modeling, to provide a coherent picture of how fibrin clots behave from the centimeter to the nanometer scale. This multi-scale strategy was vital: "You have to examine events at different spatial scales with various methodologies to understand how fibrin behaves," explains Weisel.

Protein unfolding explains how the volume of the fibers decreases as they're stretched. "When you unfold proteins, you're exposing parts that are normally buried in the middle of the molecule," Weisel says. "And these are hydrophobic; they don't want to be near water. So the unfolded protein structures interact with each other through those hydrophobic parts and water is expelled from the molecule. We see this when we stretch the fibrin and that's how the whole clot volume decreases about tenfold with threefold stretching." This great extensibility of fibrin on the molecular scale allows a fibrin clot to undergo the stretching and pulling that occurs during wound healing, while remaining permeable enough to allow itself to be broken down by enzymes when it's no longer needed.

That expulsion of water was a surprise, Weisel says. "The volume change, the fact that it's so extensible, that wasn't known previously. At the molecular level this unfolding is necessary for the mechanical properties."

The work has opened up new avenues of research that the researchers are eager to pursue. "The more we know about the mechanism of blood clotting, the greater the possibilities for learning how to control and modulate it, which may lead to new treatments of thrombotic and bleeding problems," surmises Weisel.

Beyond the obvious medical benefits, the team's interdisciplinary approach highlights the relevance of the research to other fields, such as biomedical engineering and materials science.

The study was funded by the National Heart Lung and Blood Institute, the National Science Foundation, and the Natural Sciences and Engineering Research Council of Canada.

PENN Medicine is a $3.6 billion enterprise dedicated to the related missions of medical education, biomedical research, and excellence in patient care. PENN Medicine consists of the University of Pennsylvania School of Medicine (founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System.

Penn's School of Medicine is currently ranked #3 in the nation in U.S.News & World Report's survey of top research-oriented medical schools; and, according to the National Institutes of Health, received over $366 million in NIH grants (excluding contracts) in the 2008 fiscal year. Supporting 1,700 fulltime faculty and 700 students, the School of Medicine is recognized worldwide for its superior education and training of the next generation of physician-scientists and leaders of academic medicine.

The University of Pennsylvania Health System (UPHS) includes its flagship hospital, the Hospital of the University of Pennsylvania, rated one of the nation's top ten "Honor Roll" hospitals by U.S.News & World Report; Pennsylvania Hospital, the nation's first hospital; and Penn Presbyterian Medical Center, named one of the nation's "100 Top Hospitals" for cardiovascular care by Thomson Reuters. In addition UPHS includes a primary-care provider network; a faculty practice plan; home care, hospice, and nursing home; three multispecialty satellite facilities; as well as the Penn Medicine at Rittenhouse campus, which offers comprehensive inpatient rehabilitation facilities and outpatient services in multiple specialties.

Karen Kreeger | EurekAlert!
Further information:
http://www.uphs.upenn.edu

More articles from Life Sciences:

nachricht Climate Impact Research in Hannover: Small Plants against Large Waves
17.08.2018 | Leibniz Universität Hannover

nachricht First transcription atlas of all wheat genes expands prospects for research and cultivation
17.08.2018 | Leibniz-Institut für Pflanzengenetik und Kulturpflanzenforschung

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Color effects from transparent 3D-printed nanostructures

New design tool automatically creates nanostructure 3D-print templates for user-given colors
Scientists present work at prestigious SIGGRAPH conference

Most of the objects we see are colored by pigments, but using pigments has disadvantages: such colors can fade, industrial pigments are often toxic, and...

Im Focus: Unraveling the nature of 'whistlers' from space in the lab

A new study sheds light on how ultralow frequency radio waves and plasmas interact

Scientists at the University of California, Los Angeles present new research on a curious cosmic phenomenon known as "whistlers" -- very low frequency packets...

Im Focus: New interactive machine learning tool makes car designs more aerodynamic

Scientists develop first tool to use machine learning methods to compute flow around interactively designable 3D objects. Tool will be presented at this year’s prestigious SIGGRAPH conference.

When engineers or designers want to test the aerodynamic properties of the newly designed shape of a car, airplane, or other object, they would normally model...

Im Focus: Robots as 'pump attendants': TU Graz develops robot-controlled rapid charging system for e-vehicles

Researchers from TU Graz and their industry partners have unveiled a world first: the prototype of a robot-controlled, high-speed combined charging system (CCS) for electric vehicles that enables series charging of cars in various parking positions.

Global demand for electric vehicles is forecast to rise sharply: by 2025, the number of new vehicle registrations is expected to reach 25 million per year....

Im Focus: The “TRiC” to folding actin

Proteins must be folded correctly to fulfill their molecular functions in cells. Molecular assistants called chaperones help proteins exploit their inbuilt folding potential and reach the correct three-dimensional structure. Researchers at the Max Planck Institute of Biochemistry (MPIB) have demonstrated that actin, the most abundant protein in higher developed cells, does not have the inbuilt potential to fold and instead requires special assistance to fold into its active state. The chaperone TRiC uses a previously undescribed mechanism to perform actin folding. The study was recently published in the journal Cell.

Actin is the most abundant protein in highly developed cells and has diverse functions in processes like cell stabilization, cell division and muscle...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

LaserForum 2018 deals with 3D production of components

17.08.2018 | Event News

Within reach of the Universe

08.08.2018 | Event News

A journey through the history of microscopy – new exhibition opens at the MDC

27.07.2018 | Event News

 
Latest News

Smallest transistor worldwide switches current with a single atom in solid electrolyte

17.08.2018 | Physics and Astronomy

Robots as Tools and Partners in Rehabilitation

17.08.2018 | Information Technology

Climate Impact Research in Hannover: Small Plants against Large Waves

17.08.2018 | Life Sciences

VideoLinks
Science & Research
Overview of more VideoLinks >>>