2112-P: Sarco/Endoplasmic Reticulum ATPase (SERCA2) Deficiency in the Nonobese Diabetic (NOD) Mouse Accelerates Type 1 Diabetes Development
Recent evidence has implicated pathways intrinsic to the β cell, such as endoplasmic reticulum (ER) stress, as potential triggers of T1D. ER stress is increased by the loss of ER Ca2+, leading to decreased β cell function and increased β cell apoptosis. Maintenance of intraluminal ER Ca2+ stores is...
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| Veröffentlicht in: | Diabetes (New York, N.Y.) N.Y.), 2020-06, Vol.69 (Supplement_1) |
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| container_title | Diabetes (New York, N.Y.) |
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| creator | BONE, ROBERT N. REISSAUS, CHRISTOPHER A. KONO, TATSUYOSHI EVANS-MOLINA, CARMELLA |
| description | Recent evidence has implicated pathways intrinsic to the β cell, such as endoplasmic reticulum (ER) stress, as potential triggers of T1D. ER stress is increased by the loss of ER Ca2+, leading to decreased β cell function and increased β cell apoptosis. Maintenance of intraluminal ER Ca2+ stores is primarily regulated by the sarco/endoplasmic reticulum Ca2+ ATPase (SERCA2) pump, and we have shown that β cell SERCA2 expression is reduced in islets from mouse models of T1D prior to, and after, disease onset. Thus, we hypothesized that SERCA2-mediated ER Ca2+ dyshomeostasis could be a major contributor to T1D development. To test this, we generated a mouse model haploinsufficient for SERCA2 on the NOD background (NOD-S2+/-). Compared to wild type littermates (NOD-WT), NOD-S2+/- mice had a higher incidence of diabetes (p |
| doi_str_mv | 10.2337/db20-2112-P |
| format | Article |
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ER stress is increased by the loss of ER Ca2+, leading to decreased β cell function and increased β cell apoptosis. Maintenance of intraluminal ER Ca2+ stores is primarily regulated by the sarco/endoplasmic reticulum Ca2+ ATPase (SERCA2) pump, and we have shown that β cell SERCA2 expression is reduced in islets from mouse models of T1D prior to, and after, disease onset. Thus, we hypothesized that SERCA2-mediated ER Ca2+ dyshomeostasis could be a major contributor to T1D development. To test this, we generated a mouse model haploinsufficient for SERCA2 on the NOD background (NOD-S2+/-). Compared to wild type littermates (NOD-WT), NOD-S2+/- mice had a higher incidence of diabetes (p<0.0001) and incidence was accelerated (14.5 wks vs. 19 wks, p<0.0001). Prior to diabetes onset, NOD-S2+/- islets also had increased MHC-I expression, which has been reported to follow increased ER stress and lead to increased β cell immunogenicity. To test whether SERCA2 activation may have beneficial therapeutic effects, we treated NOD-WT and NOD-S2+/- mice with CDN1163, an allosteric activator of SERCA2, from 6-8 wks of age and observed a two week delay in NOD-S2+/- average onset (p<0.05). To characterize patterns of islet immune infiltration in response to SERCA2 loss, we are utilizing the CODEX multiplexed tissue imaging platform. Our pilot study used a ten antibody panel to label and image spleen, pancreatic lymph nodes, and islets from NOD-WT. Using Indiana University-developed software, Volumetric Tissue Exploration Analysis, our preliminary analysis yields a high fidelity of nuclear segmentation and low (∼10%) false positive identification of markers. Taken together, our data suggest that loss of SERCA2 exacerbates T1D development and indicates SERCA2 may be a novel T1D therapeutic target.</description><identifier>ISSN: 0012-1797</identifier><identifier>EISSN: 1939-327X</identifier><identifier>DOI: 10.2337/db20-2112-P</identifier><language>eng</language><publisher>New York: American Diabetes Association</publisher><subject>Adenosine triphosphatase ; Allosteric properties ; Animal models ; Apoptosis ; Beta cells ; Ca2+-transporting ATPase ; Calcium (reticular) ; Calcium homeostasis ; Diabetes ; Diabetes mellitus (insulin dependent) ; Endoplasmic reticulum ; Immunogenicity ; Lymph nodes ; Major histocompatibility complex ; Pancreas ; Segmentation ; Spleen ; Therapeutic applications</subject><ispartof>Diabetes (New York, N.Y.), 2020-06, Vol.69 (Supplement_1)</ispartof><rights>Copyright American Diabetes Association Jun 1, 2020</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c1060-42de91d7e6d6353c52779e80c9c4391f3595a614084d70ef182d83e0c5cb139b3</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27923,27924</link.rule.ids></links><search><creatorcontrib>BONE, ROBERT N.</creatorcontrib><creatorcontrib>REISSAUS, CHRISTOPHER A.</creatorcontrib><creatorcontrib>KONO, TATSUYOSHI</creatorcontrib><creatorcontrib>EVANS-MOLINA, CARMELLA</creatorcontrib><title>2112-P: Sarco/Endoplasmic Reticulum ATPase (SERCA2) Deficiency in the Nonobese Diabetic (NOD) Mouse Accelerates Type 1 Diabetes Development</title><title>Diabetes (New York, N.Y.)</title><description>Recent evidence has implicated pathways intrinsic to the β cell, such as endoplasmic reticulum (ER) stress, as potential triggers of T1D. ER stress is increased by the loss of ER Ca2+, leading to decreased β cell function and increased β cell apoptosis. Maintenance of intraluminal ER Ca2+ stores is primarily regulated by the sarco/endoplasmic reticulum Ca2+ ATPase (SERCA2) pump, and we have shown that β cell SERCA2 expression is reduced in islets from mouse models of T1D prior to, and after, disease onset. Thus, we hypothesized that SERCA2-mediated ER Ca2+ dyshomeostasis could be a major contributor to T1D development. To test this, we generated a mouse model haploinsufficient for SERCA2 on the NOD background (NOD-S2+/-). Compared to wild type littermates (NOD-WT), NOD-S2+/- mice had a higher incidence of diabetes (p<0.0001) and incidence was accelerated (14.5 wks vs. 19 wks, p<0.0001). Prior to diabetes onset, NOD-S2+/- islets also had increased MHC-I expression, which has been reported to follow increased ER stress and lead to increased β cell immunogenicity. To test whether SERCA2 activation may have beneficial therapeutic effects, we treated NOD-WT and NOD-S2+/- mice with CDN1163, an allosteric activator of SERCA2, from 6-8 wks of age and observed a two week delay in NOD-S2+/- average onset (p<0.05). To characterize patterns of islet immune infiltration in response to SERCA2 loss, we are utilizing the CODEX multiplexed tissue imaging platform. Our pilot study used a ten antibody panel to label and image spleen, pancreatic lymph nodes, and islets from NOD-WT. Using Indiana University-developed software, Volumetric Tissue Exploration Analysis, our preliminary analysis yields a high fidelity of nuclear segmentation and low (∼10%) false positive identification of markers. Taken together, our data suggest that loss of SERCA2 exacerbates T1D development and indicates SERCA2 may be a novel T1D therapeutic target.</description><subject>Adenosine triphosphatase</subject><subject>Allosteric properties</subject><subject>Animal models</subject><subject>Apoptosis</subject><subject>Beta cells</subject><subject>Ca2+-transporting ATPase</subject><subject>Calcium (reticular)</subject><subject>Calcium homeostasis</subject><subject>Diabetes</subject><subject>Diabetes mellitus (insulin dependent)</subject><subject>Endoplasmic reticulum</subject><subject>Immunogenicity</subject><subject>Lymph nodes</subject><subject>Major histocompatibility complex</subject><subject>Pancreas</subject><subject>Segmentation</subject><subject>Spleen</subject><subject>Therapeutic applications</subject><issn>0012-1797</issn><issn>1939-327X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><recordid>eNotkNtKw0AQhhdRsFavfIEFb1okdg85rXehqQeobWkreBeSzQRTkmzcTYQ-gy_thpa5GObnm_mHH6F7Sp4Y58EszxhxGKXM2VygERVcOJwFX5doRIgVaSCCa3RjzIEQ4tsaob8T_Yx3qZZqtmhy1VapqUuJt9CVsq_6Gkf7TWoAT3aL7TxiUxxDUcoSGnnEZYO7b8Ar1agMLBOXaTbs4clqHU_xh-qtGEkJFei0A4P3xxYwPXN2juEXKtXW0HS36KpIKwN35z5Gny-L_fzNWa5f3-fR0pHU_uy4LAdB8wD83Ocelx4LAgEhkUK6XNCCe8JLfeqS0M0DAgUNWR5yINKTGeUi42P0cLrbavXTg-mSg-p1Yy0T5lLhei7hxFKPJ0pqZYyGIml1Waf6mFCSDGknQ9rJkF-y4f-i8m8Y</recordid><startdate>20200601</startdate><enddate>20200601</enddate><creator>BONE, ROBERT N.</creator><creator>REISSAUS, CHRISTOPHER A.</creator><creator>KONO, TATSUYOSHI</creator><creator>EVANS-MOLINA, CARMELLA</creator><general>American Diabetes Association</general><scope>AAYXX</scope><scope>CITATION</scope><scope>K9.</scope><scope>NAPCQ</scope></search><sort><creationdate>20200601</creationdate><title>2112-P: Sarco/Endoplasmic Reticulum ATPase (SERCA2) Deficiency in the Nonobese Diabetic (NOD) Mouse Accelerates Type 1 Diabetes Development</title><author>BONE, ROBERT N. ; REISSAUS, CHRISTOPHER A. ; KONO, TATSUYOSHI ; EVANS-MOLINA, CARMELLA</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c1060-42de91d7e6d6353c52779e80c9c4391f3595a614084d70ef182d83e0c5cb139b3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Adenosine triphosphatase</topic><topic>Allosteric properties</topic><topic>Animal models</topic><topic>Apoptosis</topic><topic>Beta cells</topic><topic>Ca2+-transporting ATPase</topic><topic>Calcium (reticular)</topic><topic>Calcium homeostasis</topic><topic>Diabetes</topic><topic>Diabetes mellitus (insulin dependent)</topic><topic>Endoplasmic reticulum</topic><topic>Immunogenicity</topic><topic>Lymph nodes</topic><topic>Major histocompatibility complex</topic><topic>Pancreas</topic><topic>Segmentation</topic><topic>Spleen</topic><topic>Therapeutic applications</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>BONE, ROBERT N.</creatorcontrib><creatorcontrib>REISSAUS, CHRISTOPHER A.</creatorcontrib><creatorcontrib>KONO, TATSUYOSHI</creatorcontrib><creatorcontrib>EVANS-MOLINA, CARMELLA</creatorcontrib><collection>CrossRef</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Premium</collection><jtitle>Diabetes (New York, N.Y.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>BONE, ROBERT N.</au><au>REISSAUS, CHRISTOPHER A.</au><au>KONO, TATSUYOSHI</au><au>EVANS-MOLINA, CARMELLA</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>2112-P: Sarco/Endoplasmic Reticulum ATPase (SERCA2) Deficiency in the Nonobese Diabetic (NOD) Mouse Accelerates Type 1 Diabetes Development</atitle><jtitle>Diabetes (New York, N.Y.)</jtitle><date>2020-06-01</date><risdate>2020</risdate><volume>69</volume><issue>Supplement_1</issue><issn>0012-1797</issn><eissn>1939-327X</eissn><abstract>Recent evidence has implicated pathways intrinsic to the β cell, such as endoplasmic reticulum (ER) stress, as potential triggers of T1D. ER stress is increased by the loss of ER Ca2+, leading to decreased β cell function and increased β cell apoptosis. Maintenance of intraluminal ER Ca2+ stores is primarily regulated by the sarco/endoplasmic reticulum Ca2+ ATPase (SERCA2) pump, and we have shown that β cell SERCA2 expression is reduced in islets from mouse models of T1D prior to, and after, disease onset. Thus, we hypothesized that SERCA2-mediated ER Ca2+ dyshomeostasis could be a major contributor to T1D development. To test this, we generated a mouse model haploinsufficient for SERCA2 on the NOD background (NOD-S2+/-). Compared to wild type littermates (NOD-WT), NOD-S2+/- mice had a higher incidence of diabetes (p<0.0001) and incidence was accelerated (14.5 wks vs. 19 wks, p<0.0001). Prior to diabetes onset, NOD-S2+/- islets also had increased MHC-I expression, which has been reported to follow increased ER stress and lead to increased β cell immunogenicity. To test whether SERCA2 activation may have beneficial therapeutic effects, we treated NOD-WT and NOD-S2+/- mice with CDN1163, an allosteric activator of SERCA2, from 6-8 wks of age and observed a two week delay in NOD-S2+/- average onset (p<0.05). To characterize patterns of islet immune infiltration in response to SERCA2 loss, we are utilizing the CODEX multiplexed tissue imaging platform. Our pilot study used a ten antibody panel to label and image spleen, pancreatic lymph nodes, and islets from NOD-WT. Using Indiana University-developed software, Volumetric Tissue Exploration Analysis, our preliminary analysis yields a high fidelity of nuclear segmentation and low (∼10%) false positive identification of markers. Taken together, our data suggest that loss of SERCA2 exacerbates T1D development and indicates SERCA2 may be a novel T1D therapeutic target.</abstract><cop>New York</cop><pub>American Diabetes Association</pub><doi>10.2337/db20-2112-P</doi></addata></record> |
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| source | Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central |
| subjects | Adenosine triphosphatase Allosteric properties Animal models Apoptosis Beta cells Ca2+-transporting ATPase Calcium (reticular) Calcium homeostasis Diabetes Diabetes mellitus (insulin dependent) Endoplasmic reticulum Immunogenicity Lymph nodes Major histocompatibility complex Pancreas Segmentation Spleen Therapeutic applications |
| title | 2112-P: Sarco/Endoplasmic Reticulum ATPase (SERCA2) Deficiency in the Nonobese Diabetic (NOD) Mouse Accelerates Type 1 Diabetes Development |
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