{"id":10,"date":"2019-09-09T18:53:19","date_gmt":"2019-09-09T18:53:19","guid":{"rendered":"https:\/\/lab.research.sickkids.ca\/freeman\/?page_id=10"},"modified":"2024-01-11T19:42:12","modified_gmt":"2024-01-11T19:42:12","slug":"research","status":"publish","type":"page","link":"https:\/\/lab.research.sickkids.ca\/freeman\/research\/","title":{"rendered":"PROJECTS"},"content":{"rendered":"

[vc_row][vc_column]

<\/span>Our Work<\/span><\/div><\/div>[\/vc_column][\/vc_row][vc_row full_width_row=”true” padding_left=”50px” padding_right=”50px”][vc_column parallax=”content-moving” css=”.vc_custom_1600795170292{border-radius: 4px !important;}”][vc_tta_tabs style=”modern” color=”sky” spacing=”5″ active_section=”1″ css_animation=”fadeIn”][vc_tta_section title=”Solute Transporters” tab_id=”1600359162721-fffd63d7-f954″][vc_row_inner content_placement=”middle”][vc_column_inner width=”2\/3″][vc_column_text]<\/p>\n

Once released by hydrolases in the lumen of (endo)lysosomes, the smallest components of organic cargo are transported across the membrane and into the cytosol. This is achieved by the solute carrier (SLC) group of membrane transport proteins (which include over 400 members) that are categorized into 66 families, according to the solutes they are responsible for transporting. While many of these transporters are found on the surface of cells, we are largely interested in the members of the SLC family that are located to the endolysosomal pathway. This is because 1) these transporters are poorly understood when compared to their counterparts that reside in the plasma membrane, 2) defects in these transporters can lead to lysosomal storage disorders, and 3) variants in these genes are also associated with inflammatory and neurodegenerative diseases. We are studying the mechanisms that provide the driving force and activity of select members of SLC transporters. We are also interested how these transporters regulate (and are regulated by) the physical properties of the membranes in which they reside including its tension and electrical potential.<\/p>\n

[\/vc_column_text][\/vc_column_inner][vc_column_inner width=”1\/3″][vc_single_image image=”841″ img_size=”large” alignment=”center”][\/vc_column_inner][\/vc_row_inner][\/vc_tta_section][vc_tta_section title=”Barriers to Phagocytosis” tab_id=”1600359162721-69f4c991-8375″][vc_row_inner][vc_column_inner][vc_column_text]Phagocytosis, the ingestion of particulate matter, plays an essential role in the maintenance of tissue homeostasis.\u00a0 It serves as a first line of defense in the elimination of invading pathogens.\u00a0 Phagocytosis also prevents secondary necrosis and unwanted inflammation by efficiently recognizing and disposing of apoptotic bodies and debris.\u00a0 In addition, phagocytic clearance of malignant cells is fundamental in the innate immune surveillance for cancerous growth; indeed, suppression of phagocytosis facilitates tumor-mediated immune evasion.\u00a0 Given these essential functions, phagocytes reside in virtually all tissues of the body, where they constantly survey their surroundings for prey.<\/p>\n

In their surveillance, phagocytes must rapidly distinguish harmful from healthy components by detecting features exposed on the surface of their putative targets.\u00a0 Features that trigger phagocytosis can be intrinsic to the target or facilitated by the deposition of soluble opsonins on the target. These ligands are called \u201ceat me\u201d signals as they engage phagocytic receptors that trigger extensive remodeling of the plasma membrane and of the actin cytoskeleton, culminating in the extension of pseudopods that surround and engulf the target.<\/p>\n

In addition to scanning for \u201ceat me\u201d signals, phagocytes also recognize surface molecules that serve as \u201cdon\u2019t eat me\u201d signals.\u00a0 These include CD47, PD-L1, and CD24 that engage their cognate receptors SIRP\u03b1, PD-1, and Siglec-10, respectively, to exert an inhibitory effect on phagocytosis.\u00a0 When engaged, these inhibitory receptors arrest signaling pathways by recruiting otherwise cytosolic phosphatases that suppress phagocytic signaling. \u00a0Certain tumors have found ways to usurp these mechanisms to support their growth. In addition, mucinous tumors form an elaborate barrier to the recognition of “eat me” signals and neo-antigens: the glycocalyx. This can be considered a “don’t come close to me” barrier to phagocytosis and cytolytic interactions with killer cells.<\/p>\n

While IgG-based biologics that target the \u201cdon\u2019t eat me\u201d pathways of cancerous lesions have been deployed with some success, augmenting these responses, for example by removing the glycocalyx barrier, would be advantageous.[\/vc_column_text][\/vc_column_inner][\/vc_row_inner][vc_row_inner][vc_column_inner width=”1\/2″][vc_single_image image=”266″ img_size=”full”][\/vc_column_inner][vc_column_inner width=”1\/2″][vc_single_image image=”383″ img_size=”full” add_caption=”yes”][\/vc_column_inner][\/vc_row_inner][\/vc_tta_section][vc_tta_section title=”Membrane Oxidation” tab_id=”1672768517551-1d140ef3-f309″][vc_column_text]The ongoing metabolic and microbicidal pathways that support and protect cellular life generate potentially damaging reactive oxygen species. To counteract damage, cells express peroxidases, antioxidant enzymes that catalyze the reduction of oxidized biomolecules.\u00a0A single hydroperoxidase is responsible for reducing lipid peroxides called Glutathione peroxidase 4 (GPX4); its activity is essential and its inhibition causes a unique type of lytic cell death, ferroptosis.<\/p>\n

Recently, we have been working to understand the mechanisms that lead to cell lysis in ferroptosis. Using sensors for membrane oxidation that we can image with high resolution microscopy, we found that the lipid peroxides formed during ferroptosis accumulate preferentially at the plasma membrane. The oxidation of the membrane increases in its tension, resulting in the constitutive gating mechanosensitive channels, ultimately making the membrane permeable to cations. Blocking or deleting the channels prevents ferroptosis.<\/p>\n

We\u2019re now interested in how oxidized membranes feature more generally in mechanosensitive channel gating, including for organelles.[\/vc_column_text][vc_single_image image=”786″ img_size=”full”][\/vc_tta_section][\/vc_tta_tabs][\/vc_column][\/vc_row][vc_row][vc_column][vc_separator][vc_tweetmeme][vc_facebook][\/vc_column][\/vc_row]<\/p>\n<\/div>","protected":false},"excerpt":{"rendered":"

[vc_row][vc_column][\/vc_column][\/vc_row][vc_row full_width_row=”true” padding_left=”50px” padding_right=”50px”][vc_column parallax=”content-moving” css=”.vc_custom_1600795170292{border-radius: 4px !important;}”][vc_tta_tabs style=”modern” color=”sky” spacing=”5″ active_section=”1″ css_animation=”fadeIn”][vc_tta_section title=”Solute Transporters” tab_id=”1600359162721-fffd63d7-f954″][vc_row_inner content_placement=”middle”][vc_column_inner width=”2\/3″][vc_column_text] Once released by hydrolases in the lumen of (endo)lysosomes, the smallest components of organic cargo are transported across the membrane and into the cytosol. This is achieved by the solute carrier (SLC) group of membrane transport proteins…<\/p>\n","protected":false},"author":119,"featured_media":221,"parent":0,"menu_order":0,"comment_status":"closed","ping_status":"closed","template":"","meta":{"footnotes":""},"class_list":["post-10","page","type-page","status-publish","has-post-thumbnail","hentry","description-off"],"yoast_head":"\nPROJECTS - Freeman 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:\/\/lab.research.sickkids.ca\/freeman\/research\/\" \/>\n<meta property=\"og:locale\" content=\"en_US\" \/>\n<meta property=\"og:type\" content=\"article\" \/>\n<meta property=\"og:title\" content=\"PROJECTS\" \/>\n<meta property=\"og:description\" content=\"[vc_row][vc_column][\/vc_column][\/vc_row][vc_row full_width_row=”true” padding_left=”50px” padding_right=”50px”][vc_column parallax=”content-moving” css=”.vc_custom_1600795170292{border-radius: 4px !important;}”][vc_tta_tabs style=”modern” color=”sky” spacing=”5″ active_section=”1″ css_animation=”fadeIn”][vc_tta_section title=”Solute Transporters” tab_id=”1600359162721-fffd63d7-f954″][vc_row_inner content_placement=”middle”][vc_column_inner width=”2\/3″][vc_column_text] Once released by hydrolases in the lumen of (endo)lysosomes, the smallest components of organic cargo are transported across the membrane and into the cytosol. This is achieved by the solute carrier (SLC) group of membrane transport proteins…\" \/>\n<meta property=\"og:url\" content=\"https:\/\/lab.research.sickkids.ca\/freeman\/research\/\" \/>\n<meta property=\"og:site_name\" content=\"Freeman Lab\" \/>\n<meta property=\"article:modified_time\" content=\"2024-01-11T19:42:12+00:00\" \/>\n<meta property=\"og:image\" content=\"https:\/\/lab.research.sickkids.ca\/freeman\/wp-content\/uploads\/sites\/94\/2020\/09\/macrophages-4.png\" \/>\n\t<meta property=\"og:image:width\" content=\"1920\" \/>\n\t<meta property=\"og:image:height\" content=\"1280\" \/>\n\t<meta property=\"og:image:type\" content=\"image\/png\" \/>\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=\"4 minutes\" \/>\n<script type=\"application\/ld+json\" class=\"yoast-schema-graph\">{\"@context\":\"https:\/\/schema.org\",\"@graph\":[{\"@type\":\"WebPage\",\"@id\":\"https:\/\/lab.research.sickkids.ca\/freeman\/research\/\",\"url\":\"https:\/\/lab.research.sickkids.ca\/freeman\/research\/\",\"name\":\"PROJECTS - Freeman Lab\",\"isPartOf\":{\"@id\":\"https:\/\/lab.research.sickkids.ca\/freeman\/#website\"},\"primaryImageOfPage\":{\"@id\":\"https:\/\/lab.research.sickkids.ca\/freeman\/research\/#primaryimage\"},\"image\":{\"@id\":\"https:\/\/lab.research.sickkids.ca\/freeman\/research\/#primaryimage\"},\"thumbnailUrl\":\"https:\/\/lab.research.sickkids.ca\/freeman\/wp-content\/uploads\/sites\/94\/2020\/09\/macrophages-4.png\",\"datePublished\":\"2019-09-09T18:53:19+00:00\",\"dateModified\":\"2024-01-11T19:42:12+00:00\",\"breadcrumb\":{\"@id\":\"https:\/\/lab.research.sickkids.ca\/freeman\/research\/#breadcrumb\"},\"inLanguage\":\"en-US\",\"potentialAction\":[{\"@type\":\"ReadAction\",\"target\":[\"https:\/\/lab.research.sickkids.ca\/freeman\/research\/\"]}]},{\"@type\":\"ImageObject\",\"inLanguage\":\"en-US\",\"@id\":\"https:\/\/lab.research.sickkids.ca\/freeman\/research\/#primaryimage\",\"url\":\"https:\/\/lab.research.sickkids.ca\/freeman\/wp-content\/uploads\/sites\/94\/2020\/09\/macrophages-4.png\",\"contentUrl\":\"https:\/\/lab.research.sickkids.ca\/freeman\/wp-content\/uploads\/sites\/94\/2020\/09\/macrophages-4.png\",\"width\":1920,\"height\":1280},{\"@type\":\"BreadcrumbList\",\"@id\":\"https:\/\/lab.research.sickkids.ca\/freeman\/research\/#breadcrumb\",\"itemListElement\":[{\"@type\":\"ListItem\",\"position\":1,\"name\":\"Home\",\"item\":\"https:\/\/lab.research.sickkids.ca\/freeman\/\"},{\"@type\":\"ListItem\",\"position\":2,\"name\":\"PROJECTS\"}]},{\"@type\":\"WebSite\",\"@id\":\"https:\/\/lab.research.sickkids.ca\/freeman\/#website\",\"url\":\"https:\/\/lab.research.sickkids.ca\/freeman\/\",\"name\":\"Freeman Lab\",\"description\":\"Spencer Freeman Lab | SickKids\",\"potentialAction\":[{\"@type\":\"SearchAction\",\"target\":{\"@type\":\"EntryPoint\",\"urlTemplate\":\"https:\/\/lab.research.sickkids.ca\/freeman\/?s={search_term_string}\"},\"query-input\":{\"@type\":\"PropertyValueSpecification\",\"valueRequired\":true,\"valueName\":\"search_term_string\"}}],\"inLanguage\":\"en-US\"}]}<\/script>\n<!-- \/ Yoast SEO Premium plugin. -->","yoast_head_json":{"title":"PROJECTS - Freeman Lab","robots":{"index":"index","follow":"follow","max-snippet":"max-snippet:-1","max-image-preview":"max-image-preview:large","max-video-preview":"max-video-preview:-1"},"canonical":"https:\/\/lab.research.sickkids.ca\/freeman\/research\/","og_locale":"en_US","og_type":"article","og_title":"PROJECTS","og_description":"[vc_row][vc_column][\/vc_column][\/vc_row][vc_row full_width_row=”true” padding_left=”50px” padding_right=”50px”][vc_column parallax=”content-moving” css=”.vc_custom_1600795170292{border-radius: 4px !important;}”][vc_tta_tabs style=”modern” color=”sky” spacing=”5″ active_section=”1″ css_animation=”fadeIn”][vc_tta_section title=”Solute Transporters” tab_id=”1600359162721-fffd63d7-f954″][vc_row_inner content_placement=”middle”][vc_column_inner width=”2\/3″][vc_column_text] Once released by hydrolases in the lumen of (endo)lysosomes, the smallest components of organic cargo are transported across the membrane and into the cytosol. This is achieved by the solute carrier (SLC) group of membrane transport proteins…","og_url":"https:\/\/lab.research.sickkids.ca\/freeman\/research\/","og_site_name":"Freeman Lab","article_modified_time":"2024-01-11T19:42:12+00:00","og_image":[{"width":1920,"height":1280,"url":"https:\/\/lab.research.sickkids.ca\/freeman\/wp-content\/uploads\/sites\/94\/2020\/09\/macrophages-4.png","type":"image\/png"}],"twitter_card":"summary_large_image","twitter_misc":{"Est. reading time":"4 minutes"},"schema":{"@context":"https:\/\/schema.org","@graph":[{"@type":"WebPage","@id":"https:\/\/lab.research.sickkids.ca\/freeman\/research\/","url":"https:\/\/lab.research.sickkids.ca\/freeman\/research\/","name":"PROJECTS - Freeman Lab","isPartOf":{"@id":"https:\/\/lab.research.sickkids.ca\/freeman\/#website"},"primaryImageOfPage":{"@id":"https:\/\/lab.research.sickkids.ca\/freeman\/research\/#primaryimage"},"image":{"@id":"https:\/\/lab.research.sickkids.ca\/freeman\/research\/#primaryimage"},"thumbnailUrl":"https:\/\/lab.research.sickkids.ca\/freeman\/wp-content\/uploads\/sites\/94\/2020\/09\/macrophages-4.png","datePublished":"2019-09-09T18:53:19+00:00","dateModified":"2024-01-11T19:42:12+00:00","breadcrumb":{"@id":"https:\/\/lab.research.sickkids.ca\/freeman\/research\/#breadcrumb"},"inLanguage":"en-US","potentialAction":[{"@type":"ReadAction","target":["https:\/\/lab.research.sickkids.ca\/freeman\/research\/"]}]},{"@type":"ImageObject","inLanguage":"en-US","@id":"https:\/\/lab.research.sickkids.ca\/freeman\/research\/#primaryimage","url":"https:\/\/lab.research.sickkids.ca\/freeman\/wp-content\/uploads\/sites\/94\/2020\/09\/macrophages-4.png","contentUrl":"https:\/\/lab.research.sickkids.ca\/freeman\/wp-content\/uploads\/sites\/94\/2020\/09\/macrophages-4.png","width":1920,"height":1280},{"@type":"BreadcrumbList","@id":"https:\/\/lab.research.sickkids.ca\/freeman\/research\/#breadcrumb","itemListElement":[{"@type":"ListItem","position":1,"name":"Home","item":"https:\/\/lab.research.sickkids.ca\/freeman\/"},{"@type":"ListItem","position":2,"name":"PROJECTS"}]},{"@type":"WebSite","@id":"https:\/\/lab.research.sickkids.ca\/freeman\/#website","url":"https:\/\/lab.research.sickkids.ca\/freeman\/","name":"Freeman Lab","description":"Spencer Freeman Lab | SickKids","potentialAction":[{"@type":"SearchAction","target":{"@type":"EntryPoint","urlTemplate":"https:\/\/lab.research.sickkids.ca\/freeman\/?s={search_term_string}"},"query-input":{"@type":"PropertyValueSpecification","valueRequired":true,"valueName":"search_term_string"}}],"inLanguage":"en-US"}]}},"_links":{"self":[{"href":"https:\/\/lab.research.sickkids.ca\/freeman\/wp-json\/wp\/v2\/pages\/10","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/lab.research.sickkids.ca\/freeman\/wp-json\/wp\/v2\/pages"}],"about":[{"href":"https:\/\/lab.research.sickkids.ca\/freeman\/wp-json\/wp\/v2\/types\/page"}],"author":[{"embeddable":true,"href":"https:\/\/lab.research.sickkids.ca\/freeman\/wp-json\/wp\/v2\/users\/119"}],"replies":[{"embeddable":true,"href":"https:\/\/lab.research.sickkids.ca\/freeman\/wp-json\/wp\/v2\/comments?post=10"}],"version-history":[{"count":103,"href":"https:\/\/lab.research.sickkids.ca\/freeman\/wp-json\/wp\/v2\/pages\/10\/revisions"}],"predecessor-version":[{"id":181,"href":"https:\/\/lab.research.sickkids.ca\/freeman\/wp-json\/wp\/v2\/pages\/10\/revisions\/181"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/lab.research.sickkids.ca\/freeman\/wp-json\/wp\/v2\/media\/221"}],"wp:attachment":[{"href":"https:\/\/lab.research.sickkids.ca\/freeman\/wp-json\/wp\/v2\/media?parent=10"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}