{"562601":{"#nid":"562601","#data":{"type":"news","title":"How Mechanical Force Triggers Blood Clotting at the Molecular Scale","body":[{"value":"\u003Cp\u003EUsing a unique single-molecule force measurement tool, a research team has developed a clearer understanding of how platelets sense the mechanical forces they encounter during bleeding to initiate the cascading process that leads to blood clotting.\u003C\/p\u003E\u003Cp\u003EBeyond providing a better understanding of this vital bodily process, research into a mechanoreceptor molecule that triggers clotting could provide a potential new target for therapeutic intervention. Excessive clotting can lead to heart attack and stroke \u2013 major killers worldwide \u2013 while insufficient clotting allows life-threatening bleeding.\u003C\/p\u003E\u003Cp\u003E\u201cWe have opened a new door to study how mechanical force triggers biochemical signals inside living cells,\u201d said Lining (Arnold) Ju, who was part of the team conducting the research as a Ph.D. student in the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory University.\u003C\/p\u003E\u003Cp\u003ENow a postdoctoral researcher at the University of Sydney and the Heart Research Institute, Ju worked with Georgia Tech graduate student Yunfeng Chen, to conduct the research in the laboratory of Professor Cheng Zhu in the Coulter Department. Also part of the research were Lingzhou Xue from Penn State University and Xiaoping Du from the University of Illinois at Chicago.\u003C\/p\u003E\u003Cp\u003EThe research, supported by the National Institutes of Health and the National Science Foundation, was reported July 19 in the journal \u003Cem\u003EeLife\u003C\/em\u003E. It is believed to be the first detailed mechanobiology study on how mechanical forces acting on a single molecule on a platelet are sensed and transduced into biochemical signals. Beyond blood clotting, the work could have implications for other cellular systems that respond to mechanical force.\u003C\/p\u003E\u003Cp\u003EIn the beginning of the clotting process, human platelets use a highly specialized molecule known as glycoprotein Ib\u03b1 (GPIb\u03b1) to receive mechanical signals. In a process known as mechanosensing, the mechanical information is converted into chemical signals \u2013 the release of different types of calcium ions \u2013 that alter adhesion between platelets and other components of the clotting process. Using their unique experimental equipment, the research team correlated various forces applied to the GPIb\u03b1 molecule with different chemical signals, working to understand the operation of this natural transducer built into human platelets.\u003C\/p\u003E\u003Cp\u003EHow cells sense their mechanical environment and transduce forces into biochemical signals is a crucial, yet unresolved question in mechanobiology, the researchers noted in their paper. The researchers studied how mechanical forces outside the platelets trigger the release of calcium ions inside the cells. They applied force on the GPIb\u03b1 molecule via the binding of von Willebrand factor and a mutant form of this plasma protein that causes von Willibrand Disease, a bleeding disorder.\u003C\/p\u003E\u003Cp\u003EThe researchers observed two distinct mechanical events: the unfolding of two geometrically separate domains of GPIb\u03b1. They discovered that these two events occur synergistically to relay the information about the forces acting on GPIb\u03b1, allowing the molecule to sense both the magnitude of the force and how long it is exerted.\u003C\/p\u003E\u003Cp\u003EThe two unfolding events play distinct roles in determining the quantity and quality of the signals \u2013 the strength and types of calcium ions fired by the platelet. The strength of the signal is related to the duration of the force, noted Chen, who recently obtained a Ph.D. in bioengineering and will soon be a postdoctoral fellow at The Scripps Research Institute at La Jolla, Calif.\u003C\/p\u003E\u003Cp\u003E\u201cThe GPlb\u03b1 molecule is bound to and pulled by the von Willebrand factor, which is prolonged by unfolding of one GPIb\u03b1 domain,\u201d he said. \u201cBut the strong signal type always follows the unfolding of the other GPIb\u03b1 domain, which is enhanced by prolonged pulling at a high force,\u201d Chen added. \u201cThese properties generate cooperativity \u2013 a synergistic effect that results in the highest signaling quantity and quality at an optimal force where it lasts the longest.\u201d\u003C\/p\u003E\u003Cp\u003EHowever, the researchers discovered that the von Willebrand factor mutation associated with Type 2B von Willibrand Disease abolishes the synergy between the two unfolding events, preventing the GPIb\u03b1 molecule from efficiently transducing mechanical signals into biochemical signals.\u003C\/p\u003E\u003Cp\u003E\u201cFor years, researchers had thought that the problem was solely the defect in platelet adhesion,\u201d said Zhu. \u201cBut our research reveals another defect: the mechano-sensing machinery doesn\u2019t work well in the presence of this mutation. The platelet just doesn\u2019t get the signal that would activate it.\u201d\u003C\/p\u003E\u003Cp\u003EThat knowledge could potentially lead to new treatments for the mutation, and for new drugs to help control clotting.\u003C\/p\u003E\u003Cp\u003E\u201cWe have provided some molecular evidence to suggest under what scenarios the platelet will respond abnormally,\u201d said Ju. \u201cWe hope that this could be a target for a new therapeutic agent for treatment of biomechanical thrombosis. We have provided some new molecular insights into this process.\u201d\u003C\/p\u003E\u003Cp\u003EThe unique nanotool developed by the researchers is known as the fluorescence biomembrane force probe. The probe uses a red blood cell to apply force to a single molecule on a platelet. While force is being applied, the researchers can examine the change in calcium ions released inside the platelet by fluorescence. The ability for such concurrent measurement is key to uncovering the GPIb\u03b1 mechanosensing mechanism on a live platelet.\u003C\/p\u003E\u003Cp\u003E\u201cIn this work, we visualized the conformational changes in a single protein and the subsequent signaling event inside a cell at the same time\u201d explained Ju. \u201cA GPlb\u03b1 molecule on the platelet surface was unfolded when we pulled on it with a force on the scale of piconewtons. That molecular conformational change triggers the calcium ion release in platelets instructing them to become more adhesive and more reactive.\u201d\u003C\/p\u003E\u003Cp\u003EThe two GPIb\u03b1 domains studied by the researchers exist widely in many protein families. The methods developed by Ju and collaborators in this work can be used to analyze mechano-sensing in other biological systems.\u003C\/p\u003E\u003Cp\u003E\u003Cstrong\u003ECITATION\u003C\/strong\u003E: Lining Ju, et al., \u201cCooperative unfolding of distinctive mechanoreceptor domains transduces force into signals.\u201d (eLife 2016).\u003Ca href=\u0022\/\/elifesciences.org\/content\/5\/e15447\u0022\u003E\u0026nbsp;https:\/\/elifesciences.org\/content\/5\/e15447\u003C\/a\u003E\u003C\/p\u003E\u003Cp\u003E\u003Cem\u003EThis work was supported by NIH grants HL132019, HL062350, HL080264, and HL125356, Diabetes Australia research grant G179720, a Sydney Medical School 2016 early-career researcher kickstart grant, and NSF grant DMS-1505256. The content is solely the responsibility of the authors and does not necessarily represent the official views of the funding agencies.\u003C\/em\u003E\u003C\/p\u003E\u003Cp\u003E\u003Cstrong\u003EResearch News\u003C\/strong\u003E\u003Cbr \/\u003E\u003Cstrong\u003EGeorgia Institute of Technology\u003C\/strong\u003E\u003Cbr \/\u003E\u003Cstrong\u003E177 North Avenue\u003C\/strong\u003E\u003Cbr \/\u003E\u003Cstrong\u003EAtlanta, Georgia 30332-0181 USA\u003C\/strong\u003E\u003C\/p\u003E\u003Cp\u003E\u003Cstrong\u003EMedia Relations Contacts\u003C\/strong\u003E: John Toon (404-894-6986) (\u003Ca href=\u0022mailto:jtoon@gatech.edu\u0022\u003Ejtoon@gatech.edu\u003C\/a\u003E) or Ben Brumfield (404-385-1933) (\u003Ca href=\u0022mailto:ben.brumfield@comm.gatech.edu\u0022\u003Eben.brumfield@comm.gatech.edu\u003C\/a\u003E).\u003C\/p\u003E\u003Cp\u003E\u003Cstrong\u003EWriter\u003C\/strong\u003E: John Toon\u003C\/p\u003E","summary":null,"format":"limited_html"}],"field_subtitle":"","field_summary":[{"value":"\u003Cp\u003EUsing a unique single-molecule force measurement tool, a research team has developed a clearer understanding of how platelets sense the mechanical forces they encounter during bleeding to initiate the cascading process that leads to blood clotting.\u003C\/p\u003E","format":"limited_html"}],"field_summary_sentence":[{"value":"Researchers have developed a clearer understanding of how platelets sense mechanical forces to launch the clotting process."}],"uid":"27303","created_gmt":"2016-08-15 10:06:00","changed_gmt":"2016-10-08 03:22:19","author":"John Toon","boilerplate_text":"","field_publication":"","field_article_url":"","dateline":{"date":"2016-08-15T00:00:00-04:00","iso_date":"2016-08-15T00:00:00-04:00","tz":"America\/New_York"},"extras":[],"hg_media":{"562541":{"id":"562541","type":"image","title":"Fluorescence biomembrane force probe","body":null,"created":"1471268769","gmt_created":"2016-08-15 13:46:09","changed":"1475895230","gmt_changed":"2016-10-08 02:53:50","alt":"Fluorescence biomembrane force probe","file":{"fid":"206797","name":"nanotool-micrograph.jpg","image_path":"\/sites\/default\/files\/images\/nanotool-micrograph.jpg","image_full_path":"http:\/\/www.tlwarc.hg.gatech.edu\/\/sites\/default\/files\/images\/nanotool-micrograph.jpg","mime":"image\/jpeg","size":69670,"path_740":"http:\/\/www.tlwarc.hg.gatech.edu\/sites\/default\/files\/styles\/740xx_scale\/public\/images\/nanotool-micrograph.jpg?itok=m9u1SFti"}},"562561":{"id":"562561","type":"image","title":"Researchers with force measurement tool","body":null,"created":"1471268933","gmt_created":"2016-08-15 13:48:53","changed":"1475895367","gmt_changed":"2016-10-08 02:56:07","alt":"Researchers with force measurement tool","file":{"fid":"206798","name":"mechanical-force-3709_0.jpg","image_path":"\/sites\/default\/files\/images\/mechanical-force-3709_0.jpg","image_full_path":"http:\/\/www.tlwarc.hg.gatech.edu\/\/sites\/default\/files\/images\/mechanical-force-3709_0.jpg","mime":"image\/jpeg","size":1324956,"path_740":"http:\/\/www.tlwarc.hg.gatech.edu\/sites\/default\/files\/styles\/740xx_scale\/public\/images\/mechanical-force-3709_0.jpg?itok=vNkdYi94"}},"562571":{"id":"562571","type":"image","title":"Platelet interaction schematic","body":null,"created":"1471269134","gmt_created":"2016-08-15 13:52:14","changed":"1475895367","gmt_changed":"2016-10-08 02:56:07","alt":"Platelet interaction schematic","file":{"fid":"206799","name":"schematic-injury.jpg","image_path":"\/sites\/default\/files\/images\/schematic-injury.jpg","image_full_path":"http:\/\/www.tlwarc.hg.gatech.edu\/\/sites\/default\/files\/images\/schematic-injury.jpg","mime":"image\/jpeg","size":159253,"path_740":"http:\/\/www.tlwarc.hg.gatech.edu\/sites\/default\/files\/styles\/740xx_scale\/public\/images\/schematic-injury.jpg?itok=erZpfwIh"}}},"media_ids":["562541","562561","562571"],"groups":[{"id":"1188","name":"Research Horizons"}],"categories":[{"id":"146","name":"Life Sciences and Biology"},{"id":"135","name":"Research"}],"keywords":[{"id":"23731","name":"blood clotting"},{"id":"9893","name":"Cheng Zhu"},{"id":"102021","name":"clotting"},{"id":"170583","name":"force measurement"},{"id":"170581","name":"force probe"},{"id":"248","name":"IBB"},{"id":"170582","name":"mechanosensing"},{"id":"58521","name":"platelet"}],"core_research_areas":[{"id":"39441","name":"Bioengineering and Bioscience"}],"news_room_topics":[{"id":"71891","name":"Health and Medicine"}],"event_categories":[],"invited_audience":[],"affiliations":[],"classification":[],"areas_of_expertise":[],"news_and_recent_appearances":[],"phone":[],"contact":[{"value":"\u003Cp\u003EJohn Toon\u003C\/p\u003E\u003Cp\u003EResearch News\u003C\/p\u003E\u003Cp\u003E404-894-6986\u003C\/p\u003E","format":"limited_html"}],"email":["jtoon@gatech.edu"],"slides":[],"orientation":[],"userdata":""}}}