{"id":1313,"date":"2022-05-12T14:17:08","date_gmt":"2022-05-12T12:17:08","guid":{"rendered":"http:\/\/confolab.sav.sk\/ovsb\/en\/?page_id=1313"},"modified":"2024-09-05T16:30:20","modified_gmt":"2024-09-05T14:30:20","slug":"apvv-21-0473","status":"publish","type":"page","link":"https:\/\/confolab.sav.sk\/ovsb\/en\/projects\/active-projects\/apvv-21-0473\/","title":{"rendered":"APVV-21-0473"},"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>Mutations associated with Wolfram syndrome: alternative signaling pathways for calcium and mitochondrial physiology&nbsp;&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\/rndr-michal-cagalinec-phd\/\">Michal Cagalinec<\/a><\/h3>\n<h3>Duration: July 2022 &#8211; June 2026<br \/>\nCoordinating Organization: Institute of Experimental Endocrinology BRC SAS<br \/>\nCooperating Organization: Centre of Biosciences SAS<\/h3>\n<\/td>\n<\/tr>\n<tr>\n<td>\n<h3><span class=\"H3\">Annotation:<\/span><\/h3>\n<p>Wolfram syndrome (WS), characterized by diabetes insipidus, diabetes mellitus, optical atrophy and deafness, is caused by mutations in WFS1 gene. Protein WFS1 is highly expressed in the brain and pancreas where its mutations are in line with the symptoms. Moreover, a high expression has been observed in the heart; however, in the vast majority of WS cases the cardiac symptoms have not been reported. WFS1 is localized in the membrane of endoplasmic reticulum (ER) and strongly impacts calcium metabolism, mitochondrial function and ER stress. However, the principal question about WFS1 function still remains open \u2013 why the pancreatic \u03b2-cells and neurons are affected severely in WS, and why are the alterations in myocytes jut minor, when WFS1 is highly expressed in them? Possible explanation could be a yet unresolved compensatory mechanism present in myocytes and\/or a different signalling pathway(s) when compared to neurons\/ \u03b2-cells. Therefore, the first hypothesis is: Do the calcium metabolism and mitochondrial dynamics differ in cardiac myocytes when compared to neurons and pancreatic \u03b2-cells in case of WFS1 malfunction? The majority of WS cases represent recessive mutations; however, several dominant mutations have been identified as well. Therefore the second hypothesis is: Do the calcium metabolism and mitochondrial dynamics differ in cells expressing pathogenic dominant vs. recessive Wfs1 mutations? Moreover, complete novelty of the project represents characterization of the heterozygous WFS1 deletion variant recently identified in the first Slovak WS patient at the applicant\u2019s institute. Use of up-to-date approaches including CRISPR\/Cas9 gene editing, optogenetic techniques, confocal microscopy and the know-how of the proposed research team will help to resolve the WFS1 function which will serve for development of early diagnostics and effective treatment not only for WS, but also for diabetes mellitus and highly prevalent cardiovascular diseases.\n<\/td>\n<\/tr>\n<tr>\n<td>\n<h3><span class=\"H3\">Keywords:<\/span><\/h3>\n<p>diabetes, neurodegenerative diseases, Wolfram Syndrome, Wolframin1, calcium metabolism, mitochondrial morphology, mitochondrial dynamics, confocal microscopy, Crispr\/Cas9, electron microscopy, immunofluorescence, planar lipid membranes<\/td>\n<\/tr>\n<tr>\n<td>\n<h3><span class=\"H3\">Objectives:<\/span><\/h3>\n<p>The central hypothesis of the proposed project is, whether and how:<br \/>\n1. the calcium metabolism and mitochondrial dynamics differ in cardiac myocytes when compared to neurons and pancreatic beta-cells in case of Wolframin1 malfunction and<br \/>\n2. the calcium metabolism and mitochondrial dynamics differ in pathogenic dominant vs. recessive Wolframin1 mutations.\n<\/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\/39034309\/\")'><img decoding=\"async\" class=\"alignnone wp-image-1111\" src=\"https:\/\/confolab.sav.sk\/ovsb\/wp-content\/uploads\/NatureComunication.jpg\" alt=\"FrontiersPhysiol\" width=\"75\" \/><\/a><\/td>\n<td class=\"two\">Liiv M, Vaarmann A, Safiulina D, Choubey V, Gupta R, Kuum M, Janickova L, Hodurova Z, <strong>Cagalinec M<\/strong>, Zeb A, Hickey MA, Huang YL, Gogichaishvili N, Mandel M, Plaas M, Vasar E, Loncke J, Vervliet T, Tsai TF, Bultynck G, Veksler V, Kaasik A (2024). <a href='javascript:launchRemote(\"https:\/\/pubmed.ncbi.nlm.nih.gov\/39034309\/\")'>ER calcium depletion as a key driver for impaired ER-to-mitochondria calcium transfer and mitochondrial dysfunction in Wolfram syndrome.<\/a>. <i>Nat Commun<\/i> 15: 6143. doi: 10.1038\/s41467-024-50502-x.<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n","protected":false},"excerpt":{"rendered":"<p>Mutations associated with Wolfram syndrome: alternative signaling pathways for calcium and mitochondrial physiology&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;Back Principal Investigator: Michal Cagalinec Duration: July 2022 &#8211; June 2026 Coordinating Organization:&#8230;<span class=\"excerpt_more\"><a href=\"https:\/\/confolab.sav.sk\/ovsb\/en\/projects\/active-projects\/apvv-21-0473\/\">\u010d\u00edta\u0165 \u010falej &raquo;<\/a><\/span><\/p>\n","protected":false},"author":1,"featured_media":0,"parent":198,"menu_order":70,"comment_status":"closed","ping_status":"closed","template":"","meta":[],"_links":{"self":[{"href":"https:\/\/confolab.sav.sk\/ovsb\/en\/wp-json\/wp\/v2\/pages\/1313"}],"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=1313"}],"version-history":[{"count":9,"href":"https:\/\/confolab.sav.sk\/ovsb\/en\/wp-json\/wp\/v2\/pages\/1313\/revisions"}],"predecessor-version":[{"id":1683,"href":"https:\/\/confolab.sav.sk\/ovsb\/en\/wp-json\/wp\/v2\/pages\/1313\/revisions\/1683"}],"up":[{"embeddable":true,"href":"https:\/\/confolab.sav.sk\/ovsb\/en\/wp-json\/wp\/v2\/pages\/198"}],"wp:attachment":[{"href":"https:\/\/confolab.sav.sk\/ovsb\/en\/wp-json\/wp\/v2\/media?parent=1313"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}