{"id":977,"date":"2020-01-09T16:48:56","date_gmt":"2020-01-09T15:48:56","guid":{"rendered":"http:\/\/confolab.sav.sk\/ovsb\/en\/?page_id=977"},"modified":"2024-02-16T13:14:29","modified_gmt":"2024-02-16T12:14:29","slug":"jrp-2019-836-ryrinheart","status":"publish","type":"page","link":"https:\/\/confolab.sav.sk\/ovsb\/en\/projects\/completed-projects\/jrp-2019-836-ryrinheart\/","title":{"rendered":"JRP\/2019\/836\/RyRinHeart"},"content":{"rendered":"<p><script type=\"text\/javascript\">\n<!--\nfunction launch(newURL, newName, newFeatures, orgName) {\n  var remote = open(newURL, newName, newFeatures);\n  if (remote.opener == null)\n    remote.opener = window;\n  remote.opener.name = orgName;\n  return remote;\n}\n\nfunction launchRemote(name) {\n  var address =  name;\n  myRemote = launch(address ,\n                    \"Okno\",\n                    \"height=500, width=850, left=50, top=50, alwaysLowered=0, alwaysRaised=0, channelmode=0, dependent=0, directories=0, fullscreen=0, hotkeys=1, location=0, menubar=0, resizable=0, scrollbars=0, status=0, titlebar=1, toolbar=0, z-lock=0\",\n                    \"myWindow\");\n}\n\/\/ -->>\n<\/script><\/p>\n<h2>RyRinHeart &#8211; Discovery of Ryanodine Receptor Inhibitors for Heart Diseases&nbsp; &nbsp; &nbsp; &nbsp;<button onclick=\"goBack()\">Back<\/button> <\/h2>\n<p><script>\t \t \nfunction goBack() { window.history.go(-1); }\t \t \n<\/script><\/p>\n<table border=\"0\" width=\"100%\" cellspacing=\"1\" cellpadding=\"2\">\n<tbody>\n<tr>\n<td>\n<h3>Principal Investigator: <a href=\"http:\/\/confolab.sav.sk\/ovsb\/en\/people\/researchers\/ing-alexandra-zahradnikova-drsc\/\">Alexandra Zahradn\u00edkov\u00e1<\/a><\/h3>\n<h3>Duration: January 2020 \u2013 December 2022<br \/>\nCoordinating Organization: Institute of Experimental Endocrinology, BRC SAV, Bratislava<\/h3>\n<\/td>\n<\/tr>\n<tr>\n<td>\n<h3><span class=\"H3\">Annotation:<\/span><\/h3>\n<p>Cardiac ryanodine receptors (RyR2) control the pumping function of the heart by regulating calcium release required for cardiac myocyte contraction. Many heart diseases are accompanied by disorders of calcium release. These disorders could be suppressed by drugs that prevent unwanted RyR2 activity. The aim of this project is to develop specific inhibitors, adapted to the structure of cardiac RyR2, with the potential to treat calcium handling disorders in heart disease.<br \/>\nWe will use our original knowledge of the structure of RyR2 to identify loci in the 3D-structure of RyR2 that reduce its activity by ligand binding. This will allow us to design and synthesize RyR2 inhibitors. We will test their efficacy in experiments monitoring RyR activity. The in situ efficacy of selected agents, most promising for regulation of RyR2 function, will be tested on isolated cardiac myocytes and finally on the hearts of healthy animals and animals with heart disease.<br \/>\nMethodologically, the project is based on two pillars: molecular structure simulations, molecular dynamics, and computer-assisted drug design, the main body of expertise being the Turkish side, and a wide range of experimental and theoretical methods of studying ion channel function and calcium signalling (biochemical and electrophysiological methods, confocal microscopy, mathematical modelling of dynamics of intracellular processes), where expertise will be provided by the Slovak side.<br \/>\nThe project aims to contribute to the solution of a serious medical problem using advanced technologies, original expertise and new approaches developed in collaborating laboratories.\n<\/td>\n<\/tr>\n<tr>\n<td>\n<h3><span class=\"H3\">Keywords:<\/span><\/h3>\n<p>ryanod\u00edne receptor, cardiac myocyte, calcium signalling, drug design and testing, molecular modelling, mathematical modelling, cardiac diseases<\/td>\n<\/tr>\n<tr>\n<td>\n<h3><span class=\"H3\"><strong>Objectives<\/strong>:<\/span><\/h3>\n<p>The overall aim of the project is to design a RyR2 inhibitor potentially suitable for prevention of arrhythmias in diseased heart. To achieve this goal we formulated the following specific objectives:<\/p>\n<ul>\n<li> using biochemical and biophysical methods, to increase understanding of the mechanism of RyR2 inhibition by known inhibitors <\/li>\n<li> using molecular modelling and computer-aided drug design to search for novel drugs, and using biochemical and biophysical methods to test compounds that optimize the use of RyR2 inhibitory mechanisms for preventing unwanted calcium release in cardiac myocytes <\/li>\n<li> to test the most promising compound in an in vivo model of cardiac disease in mice <\/li>\n<\/ul>\n<\/td>\n<\/tr>\n<tr>\n<td><\/td>\n<\/tr>\n<tr>\n<td>\n<h3><span class=\"H3\">Publications:<\/span><\/h3>\n<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n<table class=\"list\" border=\"0\" width=\"100%\" cellspacing=\"0\" cellpadding=\"4\">\n<tbody>\n<tr>\n<td class=\"small\"><a href='javascript:launchRemote(\"https:\/\/pubmed.ncbi.nlm.nih.gov\/36609141\/\")'><img decoding=\"async\" class=\"alignnone wp-image-1111\" src=\"http:\/\/confolab.sav.sk\/ovsb\/wp-content\/uploads\/BiophysJnew.jpg\" alt=\"FrontiersPhysiol\" width=\"75\" \/><\/a><\/td>\n<td class=\"two\"><strong>Baglaeva I<\/strong>, <strong>Iaparov B<\/strong>, <strong>Zahradnik I<\/strong>, <strong>Zahradnikova A<\/strong> (2023). <a href='javascript:launchRemote(\"https:\/\/pubmed.ncbi.nlm.nih.gov\/36609141\/\")'>Analysis of noisy transient signals based on Gaussian process regression<\/a>. <i>Biophys J<\/i> 122: 451\u2013459. doi: 10.1016\/j.bpj.2023.01.003.<\/td>\n<\/tr>\n<tr>\n<td class=\"small\"><a href='javascript:launchRemote(\"https:\/\/pubmed.ncbi.nlm.nih.gov\/35145426\/\")'><img decoding=\"async\" loading=\"lazy\" class=\"alignnone wp-image-1111\" src=\"https:\/\/confolab.sav.sk\/ovsb\/wp-content\/uploads\/FrontiersPhysiol.jpg\" alt=\"FrontiersPhysiol\" width=\"75\" height=\"17\" \/><\/a><\/td>\n<td class=\"two\"><strong>Iaparov B<\/strong>, <strong>Baglaeva I<\/strong>, <strong>Zahradnik I<\/strong>, <strong>Zahradnikova A<\/strong> (2022). <a href='javascript:launchRemote(\"https:\/\/pubmed.ncbi.nlm.nih.gov\/35145426\/\")'>Magnesium ions moderate calcium-induced calcium release in cardiac calcium release sites by binding to ryanodine receptor activation and inhibition sites<\/a>. <i>Front Physiol<\/i> 12: 805956. doi: 10.3389\/fphys.2021.805956.<\/td>\n<\/tr>\n<tr>\n<td class=\"small\" width=\"5%\"><a href='javascript:launchRemote(\"https:\/\/pubmed.ncbi.nlm.nih.gov\/33735373\/\")'><img decoding=\"async\" loading=\"lazy\" class=\"alignnone wp-image-1114\" src=\"http:\/\/confolab.sav.sk\/ovsb\/wp-content\/uploads\/m_jgp_2021_153_4.cover_.png\" alt=\"JGP\" width=\"80\" height=\"104\" \/><\/a><\/td>\n<td class=\"two\"><strong>Iaparov B<\/strong>, <strong>Zahradnik I<\/strong>, Moskvin AS, <strong>Zahradnikova A<\/strong> (2021): <a href='javascript:launchRemote(\"https:\/\/pubmed.ncbi.nlm.nih.gov\/33735373\/\")'>In silico simulations reveal that RYR distribution affects the dynamics of calcium release in cardiac myocytes<\/a>. <i>J Gen Physiol<\/i> 153: e202012685 doi: 10.1085\/jgp.202012685.<\/td>\n<\/tr>\n<tr>\n<td class=\"small\"><a href='javascript:launchRemote(\"https:\/\/www.biorxiv.org\/content\/10.1101\/2020.08.26.260968v1\")'><img decoding=\"async\" class=\"alignnone wp-image-1111\" src=\"http:\/\/confolab.sav.sk\/ovsb\/wp-content\/uploads\/bioRxiv_article.jpg\" alt=\"Prog Biophys Mol Biol\" width=\"75\" \/><\/a><\/td>\n<td class=\"two\"> <strong>Iaparov B<\/strong>, <strong>Zahradnik I<\/strong>, Moskvin AS, <strong>Zahradnikova A<\/strong> (2020): <a href='javascript:launchRemote(\"https:\/\/www.biorxiv.org\/content\/10.1101\/2020.08.26.260968v1\")'>Synergy of calcium release site determinants in control of calcium release events in cardiac myocytes<\/a>. <i>bioRXiv<\/i> :  doi: https:\/\/doi.org\/10.1101\/2020.08.26.260968.<\/td>\n<\/tr>\n<tr>\n<td class=\"small\"><a href='javascript:launchRemote(\"https:\/\/www.ncbi.nlm.nih.gov\/pubmed\/32416189\")'><img decoding=\"async\" class=\"alignnone wp-image-1111\" src=\"http:\/\/confolab.sav.sk\/ovsb\/wp-content\/uploads\/ProgBiophysMolBiol-e1590139461171.jpg\" alt=\"Prog Biophys Mol Biol\" width=\"75\" \/><\/a><\/td>\n<td class=\"two\"><strong>Zahradnikova A<\/strong>, <strong>Iaparov B<\/strong>, <strong>Zahradnik I<\/strong> (2020): <a href='javascript:launchRemote(\"https:\/\/www.ncbi.nlm.nih.gov\/pubmed\/32416189\")'>The problem of accuracy in single-channel open probability measurements<\/a>. <i>Prog Biophys Mol Biol<\/i> 157: 94-106 doi: 10.1016\/j.pbiomolbio.2020.05.002.<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n","protected":false},"excerpt":{"rendered":"<p>RyRinHeart &#8211; Discovery of Ryanodine Receptor Inhibitors for Heart Diseases&nbsp; &nbsp; &nbsp; &nbsp;Back Principal Investigator: Alexandra Zahradn\u00edkov\u00e1 Duration: January 2020 \u2013 December 2022 Coordinating Organization:&#8230;<span class=\"excerpt_more\"><a href=\"https:\/\/confolab.sav.sk\/ovsb\/en\/projects\/completed-projects\/jrp-2019-836-ryrinheart\/\">\u010d\u00edta\u0165 \u010falej &raquo;<\/a><\/span><\/p>\n","protected":false},"author":1,"featured_media":0,"parent":199,"menu_order":50,"comment_status":"closed","ping_status":"closed","template":"","meta":[],"_links":{"self":[{"href":"https:\/\/confolab.sav.sk\/ovsb\/en\/wp-json\/wp\/v2\/pages\/977"}],"collection":[{"href":"https:\/\/confolab.sav.sk\/ovsb\/en\/wp-json\/wp\/v2\/pages"}],"about":[{"href":"https:\/\/confolab.sav.sk\/ovsb\/en\/wp-json\/wp\/v2\/types\/page"}],"author":[{"embeddable":true,"href":"https:\/\/confolab.sav.sk\/ovsb\/en\/wp-json\/wp\/v2\/users\/1"}],"replies":[{"embeddable":true,"href":"https:\/\/confolab.sav.sk\/ovsb\/en\/wp-json\/wp\/v2\/comments?post=977"}],"version-history":[{"count":14,"href":"https:\/\/confolab.sav.sk\/ovsb\/en\/wp-json\/wp\/v2\/pages\/977\/revisions"}],"predecessor-version":[{"id":1602,"href":"https:\/\/confolab.sav.sk\/ovsb\/en\/wp-json\/wp\/v2\/pages\/977\/revisions\/1602"}],"up":[{"embeddable":true,"href":"https:\/\/confolab.sav.sk\/ovsb\/en\/wp-json\/wp\/v2\/pages\/199"}],"wp:attachment":[{"href":"https:\/\/confolab.sav.sk\/ovsb\/en\/wp-json\/wp\/v2\/media?parent=977"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}