{"55899":{"#nid":"55899","#data":{"type":"news","title":"New Study Reveals Ways to Better Inhibit Blood Clots","body":[{"value":"\u003Cp\u003EFibrin, the primary ingredient of blood clots, creates a fibrous network that stems the loss of blood at an injury site. But beyond this essential work, fibrin can also cause heart attack, stroke and tissue damage by forming clots that block blood vessels.\u003C\/p\u003E\u003Cp\u003EFibrin forms when an enzyme removes parts of a blood protein called fibrinogen, exposing \u201cknobs\u201d that fit into \u201choles\u201d located on both ends of fibrinogen molecules. Uncovering these knobs allows the fibrinogen molecules to attach to one another, forming a fibrin network. To inhibit unwanted fibrin formation, researchers have developed synthetic knobs to fill the holes, but the best amino acid sequence and structure for these knobs have not been well investigated. \u003C\/p\u003E\u003Cp\u003EA new study published online in the journal \u003Cem\u003EBlood\u003C\/em\u003E reveals factors that could improve the binding of synthetic fibrin knobs to holes and the structures of these knobs in solution. The study also identifies a novel synthetic knob that displays a 10-fold higher affinity for fibrinogen holes than current synthetic knobs. This research was supported by the National Institutes of Health and the Wallace H. Coulter Foundation. \u003C\/p\u003E\u003Cp\u003E\u201cUnderstanding the fundamentals of this knob-hole interaction will lead to a more thorough knowledge of fibrin assembly mechanisms and allow us to establish criteria for designing superior anticoagulants with high hole affinity that can inhibit fibrin assembly,\u201d said Thomas Barker, an assistant professor in the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory University.\u003C\/p\u003E\u003Cp\u003EBarker, postdoctoral fellow Sarah Stabenfeldt and School of Computational Science and Engineering graduate student Jared Gossett investigated the interactions between holes and short synthetic peptides modeled after real fibrin knob sequences. They focused specifically on modeling the binding interaction and characterizing the structure of the peptides in solution. \u003C\/p\u003E\u003Cp\u003EUsing a technique called surface plasmon resonance, the research team explored the role of structural and electrostatic properties in regulating the binding of knobs to holes. The structural properties of knob peptides in an aqueous environment had not been examined previously because the small peptides could not be crystallized for structural X-ray studies. \u003C\/p\u003E\u003Cp\u003E\u201cResearchers previously measured how knob molecules bound to holes in a saturated solution,\u201d explained Barker, \u201cbut we wanted to know how fast the knobs were binding to the holes and the length of time the knob and hole interacted to determine if we could optimize these parameters to inhibit fibrin formation.\u201d \u003C\/p\u003E\u003Cp\u003EThe researchers measured the hole binding characteristics of six different knob sequences -- each seven or eight amino acids in length -- to evaluate the impact of additional backbone stabilization and\/or different charge distributions. They found that the binding rates improved significantly by adding two amino acids, called proline and phenylalanine, for stabilization and having charged configurations in the sixth and seventh positions in the sequences. \u003C\/p\u003E\u003Cp\u003E\u201cInvestigating these binding events under dynamic conditions provided critical information, but the results didn\u2019t really surprise us,\u201d noted Barker. \u201cSmall peptides in aqueous solutions \u2018wiggle\u2019 a lot, so the more stable the molecules are in their active structural state, the better chance they have of establishing a good knob-hole interaction because they\u2019re not changing their shape as much.\u201d \u003C\/p\u003E\u003Cp\u003EAnalyzing the structural dynamics of the peptides through simulation indicated that the orientation of the arginine amino acid side chain and backbone stability contributed significantly to functional binding of the knobs and holes.\u003C\/p\u003E\u003Cp\u003EDuring their investigation, the researchers also identified a novel knob peptide mimic (GPRPFPAC) that exhibited a binding rate to holes one order of magnitude higher than previously published knob sequences -- even surpassing the binding activity of the gold standard mimic (GPRPAAC). Future studies will involve modifying this novel peptide further to enhance its ability to inhibit fibrin formation for applications when blood clotting is undesirable. \u003C\/p\u003E\u003Cp\u003EThe surface plasmon resonance and modeling techniques used in this study enable peptide sequences to be modified and optimized to control the typical wound healing matrix. \u003C\/p\u003E\u003Cp\u003E\u201cAn additional goal for this technology is to develop a viable delivery strategy for synthetically engineered fibrin glue so that we can guide and control the body\u2019s response to an injury,\u201d added Barker. \u003C\/p\u003E\u003Cp\u003EShuming Nie, the Wallace H. Coulter Distinguished Faculty Chair in Biomedical Engineering, and Steve Harvey, a professor in Georgia Tech\u2019s School of Biology, also contributed to this research. \u003C\/p\u003E\u003Cp\u003E\u003Cem\u003EThis project is supported by the National Institutes of Health (NIH) (Award Nos. 1R21EB008463 and K12GM0007680). The content is solely the responsibility of the principal investigator and does not necessarily represent the official view of the NIH.\u003C\/em\u003E \u003C\/p\u003E\u003Cp\u003E\u003Cstrong\u003EResearch News \u0026amp; Publications Office\u003Cbr \/\u003EGeorgia Institute of Technology\u003Cbr \/\u003E75 Fifth Street, N.W., Suite 314\u003Cbr \/\u003EAtlanta, Georgia 30308 USA\u0026nbsp;\u003C\/strong\u003E\u003C\/p\u003E\u003Cp\u003E\u003Cstrong\u003EMedia Relations Contacts:\u003C\/strong\u003E Abby Vogel (avogel@gatech.edu; 404-385-3364) or John Toon (jtoon@gatech.edu; 404-894-6986)\u003C\/p\u003E\u003Cp\u003E\u003Cstrong\u003EWriter:\u003C\/strong\u003E Abby Vogel\u003C\/p\u003E","summary":null,"format":"limited_html"}],"field_subtitle":"","field_summary":[{"value":"\u003Cp\u003EA new study reveals factors that improve the activity of synthetic fibrin \u201cknobs\u201d, which bind to \u201choles\u201d on fibrinogen molecules to prevent blood clot formation. It also identifies a knob mimic with a 10-fold higher affinity for holes than current mimics.\u003C\/p\u003E","format":"limited_html"}],"field_summary_sentence":[{"value":"Researchers create better blood clot inhibitors"}],"uid":"27206","created_gmt":"2010-05-18 00:00:00","changed_gmt":"2016-10-08 03:05:57","author":"Abby Vogel Robinson","boilerplate_text":"","field_publication":"","field_article_url":"","dateline":{"date":"2010-05-19T00:00:00-04:00","iso_date":"2010-05-19T00:00:00-04:00","tz":"America\/New_York"},"extras":[],"hg_media":{"55900":{"id":"55900","type":"image","title":"Thomas Barker Sarah Stabenfeldt","body":null,"created":"1449175598","gmt_created":"2015-12-03 20:46:38","changed":"1475894496","gmt_changed":"2016-10-08 02:41:36","alt":"Thomas Barker Sarah Stabenfeldt","file":{"fid":"190411","name":"tpb83128.jpg","image_path":"\/sites\/default\/files\/images\/tpb83128_0.jpg","image_full_path":"http:\/\/www.tlwarc.hg.gatech.edu\/\/sites\/default\/files\/images\/tpb83128_0.jpg","mime":"image\/jpeg","size":1155140,"path_740":"http:\/\/www.tlwarc.hg.gatech.edu\/sites\/default\/files\/styles\/740xx_scale\/public\/images\/tpb83128_0.jpg?itok=ms-Oytau"}},"55901":{"id":"55901","type":"image","title":"Structure knob mimics","body":null,"created":"1449175598","gmt_created":"2015-12-03 20:46:38","changed":"1475894496","gmt_changed":"2016-10-08 02:41:36","alt":"Structure knob mimics","file":{"fid":"190412","name":"tkt29529.jpg","image_path":"\/sites\/default\/files\/images\/tkt29529_0.jpg","image_full_path":"http:\/\/www.tlwarc.hg.gatech.edu\/\/sites\/default\/files\/images\/tkt29529_0.jpg","mime":"image\/jpeg","size":86253,"path_740":"http:\/\/www.tlwarc.hg.gatech.edu\/sites\/default\/files\/styles\/740xx_scale\/public\/images\/tkt29529_0.jpg?itok=rxpDuXU_"}},"55902":{"id":"55902","type":"image","title":"Thomas Barker biomedical engineering","body":null,"created":"1449175598","gmt_created":"2015-12-03 20:46:38","changed":"1475894496","gmt_changed":"2016-10-08 02:41:36","alt":"Thomas Barker biomedical engineering","file":{"fid":"190413","name":"tgi83128.jpg","image_path":"\/sites\/default\/files\/images\/tgi83128_0.jpg","image_full_path":"http:\/\/www.tlwarc.hg.gatech.edu\/\/sites\/default\/files\/images\/tgi83128_0.jpg","mime":"image\/jpeg","size":1100665,"path_740":"http:\/\/www.tlwarc.hg.gatech.edu\/sites\/default\/files\/styles\/740xx_scale\/public\/images\/tgi83128_0.jpg?itok=Ew5ftm3Y"}}},"media_ids":["55900","55901","55902"],"related_links":[{"url":"http:\/\/bloodjournal.hematologylibrary.org\/cgi\/content\/abstract\/blood-2009-11-251801v1","title":"Blood article"},{"url":"http:\/\/www.bme.gatech.edu\/facultystaff\/faculty_record.php?id=96","title":"Thomas Barker"},{"url":"http:\/\/www.bme.gatech.edu\/","title":"Wallace H. Coulter Department of Biomedical Engineering"}],"groups":[{"id":"1188","name":"Research Horizons"}],"categories":[{"id":"146","name":"Life Sciences and Biology"},{"id":"135","name":"Research"}],"keywords":[{"id":"9319","name":"Blood Clot"},{"id":"9317","name":"Fibrin"},{"id":"9324","name":"fibrin knob"},{"id":"9318","name":"Fibrinogen"},{"id":"9322","name":"GPRPAAC"},{"id":"9321","name":"GPRPFPAC"},{"id":"7275","name":"regeneration"},{"id":"9323","name":"Repair"},{"id":"170967","name":"surface plasmon resonance"},{"id":"170968","name":"synthetic"}],"core_research_areas":[],"news_room_topics":[],"event_categories":[],"invited_audience":[],"affiliations":[],"classification":[],"areas_of_expertise":[],"news_and_recent_appearances":[],"phone":[],"contact":[{"value":"\u003Cp\u003E\u003Cstrong\u003EAbby Vogel\u003C\/strong\u003E\u003Cbr \/\u003EResearch News and Publications\u003Cbr \/\u003E\u003Ca href=\u0022http:\/\/www.gatech.edu\/contact\/index.html?id=avogel6\u0022\u003EContact Abby Vogel\u003C\/a\u003E\u003Cbr \/\u003E\u003Cstrong\u003E404-385-3364\u003C\/strong\u003E\u003C\/p\u003E","format":"limited_html"}],"email":["avogel@gatech.edu"],"slides":[],"orientation":[],"userdata":""}}}