{"id":5,"date":"2017-06-21T15:13:49","date_gmt":"2017-06-21T15:13:49","guid":{"rendered":"https:\/\/med-template.sites.unc.edu\/home\/"},"modified":"2024-11-15T11:30:37","modified_gmt":"2024-11-15T16:30:37","slug":"home","status":"publish","type":"page","link":"https:\/\/www.med.unc.edu\/pharm\/nicholaslab\/","title":{"rendered":"Home"},"content":{"rendered":"<h1>Our Research<\/h1>\n<p>Our research focuses on Antibiotic Resistance Mechanisms in <em>Neisseria gonorrheae<\/em> and P2Y receptors<\/p>\n<ul>\n<li><b>Antibiotic Resistance in Neisseria gonorrhoeae<\/b>\n<ul>\n<li>Mechanisms of chromosomally mediated antibiotic resistance<\/li>\n<li>Biological fitness consequences of acquiring resistance to cephalosporins and compensatory mutations that increase fitness of resistant strains<\/li>\n<li>Development of\u00a0novel antimicrobials for treatment of <em>N. gonorrhoeae<\/em> infections<\/li>\n<li style=\"list-style-type: none;\">\u00a0<\/li>\n<\/ul>\n<\/li>\n<\/ul>\n<ul>\n<li><b>P2Y Receptors<\/b><b><\/b>\n<ul>\n<li>Regulation of P2Y Receptor signaling in platelets<\/li>\n<li>Signaling mechanisms of P2Y receptors<\/li>\n<\/ul>\n<\/li>\n<\/ul>\n<h2>Antibiotic Resistance Mechanisms<\/h2>\n<figure id=\"attachment_2291\" class=\"thumbnail wp-caption aligncenter\" style=\"width: 810px\"><a href=\"https:\/\/www.med.unc.edu\/pharm\/nicholaslab\/wp-content\/uploads\/sites\/1372\/2023\/09\/Antibiotic-Resistance-Mechanisms1-1000.jpg\"><img loading=\"lazy\" decoding=\"async\" class=\"wp-image-2291\" src=\"https:\/\/www.med.unc.edu\/pharm\/nicholaslab\/wp-content\/uploads\/sites\/1372\/2023\/09\/Antibiotic-Resistance-Mechanisms1-1000-300x225.jpg\" alt=\"A diagram showing GC Resistance\" width=\"800\" height=\"600\" srcset=\"https:\/\/www.med.unc.edu\/pharm\/nicholaslab\/wp-content\/uploads\/sites\/1372\/2023\/09\/Antibiotic-Resistance-Mechanisms1-1000-300x225.jpg 300w, https:\/\/www.med.unc.edu\/pharm\/nicholaslab\/wp-content\/uploads\/sites\/1372\/2023\/09\/Antibiotic-Resistance-Mechanisms1-1000-768x576.jpg 768w, https:\/\/www.med.unc.edu\/pharm\/nicholaslab\/wp-content\/uploads\/sites\/1372\/2023\/09\/Antibiotic-Resistance-Mechanisms1-1000-280x210.jpg 280w, https:\/\/www.med.unc.edu\/pharm\/nicholaslab\/wp-content\/uploads\/sites\/1372\/2023\/09\/Antibiotic-Resistance-Mechanisms1-1000-600x450.jpg 600w, https:\/\/www.med.unc.edu\/pharm\/nicholaslab\/wp-content\/uploads\/sites\/1372\/2023\/09\/Antibiotic-Resistance-Mechanisms1-1000.jpg 1000w\" sizes=\"auto, (max-width: 800px) 100vw, 800px\" \/><\/a><figcaption class=\"caption wp-caption-text\">FIgure 1. Mechanisms of chromosomally mediated cephalosporin resistance in <i>Neisseria gonorrhoeae<\/i><\/figcaption><\/figure>\n<p>My laboratory is focused on elucidating the mechanisms of antibiotic resistance in the pathogenic bacterium,\u00a0<em>Neisseria gonorrhoeae<\/em>, the etiologic agent of the sexually transmitted infection, gonorrhea. In the last decade, the gonorrhea infection rate in the US has more than doubled. Complications arising from untreated infections include pelvic inflammatory disease (PID) and ectopic pregnancies in females, and gonococcal arthritis and an increased risk of both contracting and transmitting HIV in both sexes.<\/p>\n<p>Over the past several decades, the steady and inexorable increase of resistance in this organism toward multiple classes of antibiotics, including penicillin, tetracyclines, macrolides, and fluoroquinolones, has severely restricted treatment options for gonorrhea infections. Recently, strains resistant to ceftriaxone, the last remaining effective antibiotic, have emerged, portending an era of untreatable gonorrhea.<\/p>\n<p>Nearly all strains resistant to ceftriaxone contain a highly mosaic\u00a0<em>penA<\/em>\u00a0gene encoding penicillin-binding protein 2 (PBP2), the lethal target of ceftriaxone, with over 60 amino acid mutations. It is the primary determinant of resistance to cephalosporins. Other mutations include <em>mtr<\/em>, which increases expression of the MtrCDE efflux pump, and <em>penB<\/em>, which encodes mutations in the major outer membrane porin, PIB (fig. 1).<\/p>\n<p>We are investigating the structural mechanisms of resistance of PBP2, how the presence of a highly altered PBP2 impacts biological fitness and pathogenesis, and identifying compensatory mutations arising in the mouse model of gonococcal infection that increase fitness of mosaic\u00a0<em>penA<\/em>-containing strains.<\/p>\n<h2>Platelet P2Y Receptor Regulation<\/h2>\n<figure id=\"attachment_2292\" class=\"thumbnail wp-caption aligncenter\" style=\"width: 410px\"><a href=\"https:\/\/www.med.unc.edu\/pharm\/nicholaslab\/wp-content\/uploads\/sites\/1372\/2023\/09\/Platelet-activation-1000.jpg\"><img loading=\"lazy\" decoding=\"async\" class=\"wp-image-2292\" src=\"https:\/\/www.med.unc.edu\/pharm\/nicholaslab\/wp-content\/uploads\/sites\/1372\/2023\/09\/Platelet-activation-1000-225x300.jpg\" alt=\"A diagram of Platelet P2Y Receptor Regulation\" width=\"400\" height=\"533\" srcset=\"https:\/\/www.med.unc.edu\/pharm\/nicholaslab\/wp-content\/uploads\/sites\/1372\/2023\/09\/Platelet-activation-1000-225x300.jpg 225w, https:\/\/www.med.unc.edu\/pharm\/nicholaslab\/wp-content\/uploads\/sites\/1372\/2023\/09\/Platelet-activation-1000-768x1024.jpg 768w, https:\/\/www.med.unc.edu\/pharm\/nicholaslab\/wp-content\/uploads\/sites\/1372\/2023\/09\/Platelet-activation-1000-600x800.jpg 600w, https:\/\/www.med.unc.edu\/pharm\/nicholaslab\/wp-content\/uploads\/sites\/1372\/2023\/09\/Platelet-activation-1000.jpg 1000w\" sizes=\"auto, (max-width: 400px) 100vw, 400px\" \/><\/a><figcaption class=\"caption wp-caption-text\">Figure 2. Mechanism of ADP-promoted platelet aggregation<\/figcaption><\/figure>\n<p>P2Y receptors are important receptors in platelet biology. When platelets encounter underlying tissue following disruption of the blood vessel, they form a small platelet clot due to the action of thrombin on PAR receptors on platelets. These platelets also release dense granules containing secondary mediators, resulting in additional aggregation of passing platelets and formation of a platelet plug. One of the most important of these mediators is ADP, which acts on two P2Y receptors: P2Y<sub>1<\/sub>\u00a0and P2Y<sub>12<\/sub>. The P2Y<sub>1<\/sub>\u00a0receptor couples to Gq, mobilizes intracellular Ca<sup>2+<\/sup>, and activates PKC, whereas the P2Y<sub>12<\/sub>\u00a0receptor couples to Gi and inhibition of adenylyl cyclase (the P2Y<sub>12 <\/sub>receptor is the target of the anti-platelet drug Plavix). Simultaneous activation of these two receptors is required for aggregation (Fig. 2). The P2Y<sub>1<\/sub>\u00a0receptor is uniquely regulated and rapidly desensitizes (t<sub>1\/2<\/sub>\u00a0of ~18 sec), preventing further aggregation. We are investigating the molecular mechanisms of this rapid desensitization in knock-in mice expressing a non-desensitizing receptor mutant receptor.<\/p>\n<p>Figure 2. Diagram of the simultaneous activation of P2Y<sub>1<\/sub> and P2Y<sub>12<\/sub> receptors leading to platelet aggregation.<\/p>\n<h1>Publications<\/h1>\n<p><strong><a class=\"external-link\" title=\"\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/sites\/myncbi\/10ap9uOKouf\/bibliography\/40331898\/public\/?sort=date&amp;direction=descending\" rel=\"noopener\">View complete list of publications in NCBI library<\/a><\/strong><\/p>\n","protected":false},"excerpt":{"rendered":"<p>Our Research Our research focuses on Antibiotic Resistance Mechanisms in Neisseria gonorrheae and P2Y receptors Antibiotic Resistance in Neisseria gonorrhoeae Mechanisms of chromosomally mediated antibiotic resistance Biological fitness consequences of acquiring resistance to cephalosporins and compensatory mutations that increase fitness of resistant strains Development of\u00a0novel antimicrobials for treatment of N. gonorrhoeae infections \u00a0 P2Y Receptors &hellip; <a href=\"https:\/\/www.med.unc.edu\/pharm\/nicholaslab\/\" aria-label=\"Read more about Home\">Read more<\/a><\/p>\n","protected":false},"author":1369,"featured_media":0,"parent":0,"menu_order":0,"comment_status":"closed","ping_status":"closed","template":"templates\/front-page.php","meta":{"_acf_changed":false,"footnotes":"","_links_to":"","_links_to_target":""},"class_list":["post-5","page","type-page","status-publish","hentry","odd"],"acf":[],"yoast_head":"<!-- This site is optimized with the Yoast SEO plugin v26.8 - https:\/\/yoast.com\/product\/yoast-seo-wordpress\/ -->\n<title>Home - Nicholas Lab<\/title>\n<meta name=\"robots\" content=\"index, follow, max-snippet:-1, max-image-preview:large, max-video-preview:-1\" \/>\n<link rel=\"canonical\" href=\"https:\/\/www.med.unc.edu\/pharm\/nicholaslab\/\" \/>\n<meta property=\"og:locale\" content=\"en_US\" \/>\n<meta property=\"og:type\" content=\"article\" \/>\n<meta property=\"og:title\" content=\"Home - Nicholas Lab\" \/>\n<meta property=\"og:description\" content=\"Our Research Our research focuses on Antibiotic Resistance Mechanisms in Neisseria gonorrheae and P2Y receptors Antibiotic Resistance in Neisseria gonorrhoeae Mechanisms of chromosomally mediated antibiotic resistance Biological fitness consequences of acquiring resistance to cephalosporins and compensatory mutations that increase fitness of resistant strains Development of\u00a0novel antimicrobials for treatment of N. gonorrhoeae infections \u00a0 P2Y Receptors &hellip; Read more\" \/>\n<meta property=\"og:url\" content=\"https:\/\/www.med.unc.edu\/pharm\/nicholaslab\/\" \/>\n<meta property=\"og:site_name\" content=\"Nicholas Lab\" \/>\n<meta property=\"article:modified_time\" content=\"2024-11-15T16:30:37+00:00\" \/>\n<meta property=\"og:image\" content=\"https:\/\/www.med.unc.edu\/pharm\/nicholaslab\/wp-content\/uploads\/sites\/1372\/2023\/09\/Antibiotic-Resistance-Mechanisms1-1000-300x225.jpg\" \/>\n<meta name=\"twitter:card\" content=\"summary_large_image\" \/>\n<meta name=\"twitter:label1\" content=\"Est. reading time\" \/>\n\t<meta name=\"twitter:data1\" content=\"3 minutes\" \/>\n<script type=\"application\/ld+json\" class=\"yoast-schema-graph\">{\"@context\":\"https:\/\/schema.org\",\"@graph\":[{\"@type\":\"WebPage\",\"@id\":\"https:\/\/www.med.unc.edu\/pharm\/nicholaslab\/\",\"url\":\"https:\/\/www.med.unc.edu\/pharm\/nicholaslab\/\",\"name\":\"Home - Nicholas Lab\",\"isPartOf\":{\"@id\":\"https:\/\/www.med.unc.edu\/pharm\/nicholaslab\/#website\"},\"primaryImageOfPage\":{\"@id\":\"https:\/\/www.med.unc.edu\/pharm\/nicholaslab\/#primaryimage\"},\"image\":{\"@id\":\"https:\/\/www.med.unc.edu\/pharm\/nicholaslab\/#primaryimage\"},\"thumbnailUrl\":\"https:\/\/www.med.unc.edu\/pharm\/nicholaslab\/wp-content\/uploads\/sites\/1372\/2023\/09\/Antibiotic-Resistance-Mechanisms1-1000-300x225.jpg\",\"datePublished\":\"2017-06-21T15:13:49+00:00\",\"dateModified\":\"2024-11-15T16:30:37+00:00\",\"breadcrumb\":{\"@id\":\"https:\/\/www.med.unc.edu\/pharm\/nicholaslab\/#breadcrumb\"},\"inLanguage\":\"en-US\",\"potentialAction\":[{\"@type\":\"ReadAction\",\"target\":[\"https:\/\/www.med.unc.edu\/pharm\/nicholaslab\/\"]}]},{\"@type\":\"ImageObject\",\"inLanguage\":\"en-US\",\"@id\":\"https:\/\/www.med.unc.edu\/pharm\/nicholaslab\/#primaryimage\",\"url\":\"https:\/\/www.med.unc.edu\/pharm\/nicholaslab\/wp-content\/uploads\/sites\/1372\/2023\/09\/Antibiotic-Resistance-Mechanisms1-1000.jpg\",\"contentUrl\":\"https:\/\/www.med.unc.edu\/pharm\/nicholaslab\/wp-content\/uploads\/sites\/1372\/2023\/09\/Antibiotic-Resistance-Mechanisms1-1000.jpg\",\"width\":1000,\"height\":750,\"caption\":\"FIgure 1. 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