{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,2,21]],"date-time":"2025-02-21T11:59:00Z","timestamp":1740139140557,"version":"3.37.3"},"reference-count":47,"publisher":"American Physiological Society","issue":"5","funder":[{"name":"HHS | NIH | Office of Disease Prevention (ODP)","award":["R24 OD018259-02"],"award-info":[{"award-number":["R24 OD018259-02"]}]},{"name":"CTSA","award":["UL1TR000039 (CTSA)"],"award-info":[{"award-number":["UL1TR000039 (CTSA)"]}]},{"name":"HHS | NIH | National Center for Research Resources (NCRR)","award":["S10RR027897"],"award-info":[{"award-number":["S10RR027897"]}]},{"name":"UAMS Department of Pathology"},{"name":"UMMS Sabbatical Award"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["American Journal of Physiology-Gastrointestinal and Liver Physiology"],"published-print":{"date-parts":[[2016,11,1]]},"abstract":"<jats:p>Knockout technology has proven useful for delineating functional roles of specific genes. Here we describe and provide an explanation for striking pathology that occurs in a subset of genetically engineered mice expressing a rat Ca<jats:sub>V<\/jats:sub>\u03b22a transgene under control of the cardiac \u03b1-myosin heavy chain promoter. Lesions were limited to mice homozygous for transgene and independent of native Cacnb2 genomic copy number. Gross findings included an atrophied pancreas; decreased adipose tissue; thickened, orange intestines; and enlarged liver, spleen, and abdominal lymph nodes. Immune cell infiltration and cell engulfment by macrophages were associated with loss of pancreatic acinar cells. Foamy macrophages diffusely infiltrated the small intestine's lamina propria, while similar macrophage aggregates packed liver and splenic red pulp sinusoids. Periodic acid-Schiff-positive, diastase-resistant, iron-negative, Oil Red O-positive, and autofluorescent cytoplasm was indicative of a lipid storage disorder. Electron microscopic analysis revealed liver sinusoids distended by clusters of macrophages containing intracellular myelin \u201cswirls\u201d and hepatocytes with enlarged lysosomes. Additionally, build up of cholesterol, cholesterol esters, and triglycerides, along with changes in liver metabolic enzyme levels, were consistent with a lipid processing defect. Because of this complex pathology, we examined the transgene insertion site. Multiple transgene copies inserted into chromosome 19; at this same site, an approximate 180,000 base pair deletion occurred, ablating cholesterol 25-hydroxylase and partially deleting lysosomal acid lipase and CD95. Loss of gene function can account for the altered lipid processing, along with hypertrophy of the immune system, which define this phenotype, and serendipitously provides a novel mouse model of lysosomal storage disorder.<\/jats:p>","DOI":"10.1152\/ajpgi.00313.2015","type":"journal-article","created":{"date-parts":[[2016,9,23]],"date-time":"2016-09-23T03:08:46Z","timestamp":1474600126000},"page":"G903-G919","source":"Crossref","is-referenced-by-count":2,"title":["A novel transgenic mouse model of lysosomal storage disorder"],"prefix":"10.1152","volume":"311","author":[{"given":"Sonia","family":"Ortiz-Miranda","sequence":"first","affiliation":[{"name":"Cummings School of Veterinary Medicine, Tufts University, Grafton, Massachusetts;"},{"name":"Department of Microbiology &amp; Physiological Systems, University of Massachusetts Medical School, Worcester, Massachusetts;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rui","family":"Ji","sequence":"additional","affiliation":[{"name":"Departments of Biochemistry &amp; Molecular Genetics and Ophthalmology &amp; Visual Science, University of Louisville, Louisville, Kentucky;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Agata","family":"Jurczyk","sequence":"additional","affiliation":[{"name":"Diabetes Center of Excellence, University of Massachusetts Medical School, Worcester, Massachusetts;"},{"name":"Department of Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ken-Edwin","family":"Aryee","sequence":"additional","affiliation":[{"name":"Diabetes Center of Excellence, University of Massachusetts Medical School, Worcester, Massachusetts;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shunyan","family":"Mo","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, Massachusetts;"},{"name":"Proteomics and Mass Spectrometry Facility, University of Massachusetts Medical School, Worcester, Massachusetts; and"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Terry","family":"Fletcher","sequence":"additional","affiliation":[{"name":"Departments of Pharmacology &amp; Toxicology and Pathology, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Scott A.","family":"Shaffer","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, Massachusetts;"},{"name":"Proteomics and Mass Spectrometry Facility, University of Massachusetts Medical School, Worcester, Massachusetts; and"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dale L.","family":"Greiner","sequence":"additional","affiliation":[{"name":"Diabetes Center of Excellence, University of Massachusetts Medical School, Worcester, Massachusetts;"},{"name":"Department of Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rita","family":"Bortell","sequence":"additional","affiliation":[{"name":"Diabetes Center of Excellence, University of Massachusetts Medical School, Worcester, Massachusetts;"},{"name":"Department of Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ronald G.","family":"Gregg","sequence":"additional","affiliation":[{"name":"Departments of Biochemistry &amp; Molecular Genetics and Ophthalmology &amp; Visual Science, University of Louisville, Louisville, Kentucky;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alan","family":"Cheng","sequence":"additional","affiliation":[{"name":"Departments of Biochemistry &amp; Molecular Genetics and Ophthalmology &amp; Visual Science, University of Louisville, Louisville, Kentucky;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Leah J.","family":"Hennings","sequence":"additional","affiliation":[{"name":"Departments of Pharmacology &amp; Toxicology and Pathology, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7446-230X","authenticated-orcid":false,"given":"Ann R.","family":"Rittenhouse","sequence":"additional","affiliation":[{"name":"Department of Microbiology &amp; Physiological Systems, University of Massachusetts Medical School, Worcester, Massachusetts;"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"24","reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1038\/ng1195-294"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cytogfr.2008.04.001"},{"key":"B3","first-page":"1595","volume":"43","author":"Ball SL","year":"2002","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0909142106"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-3476(77)80557-X"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2012.11.004"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1016\/j.prp.2003.11.001"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.cellbio.16.1.521"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1023\/A:1021941706726"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2002.018515"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1194\/jlr.M900107-JLR200"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1194\/jlr.M700482-JLR200"},{"key":"B13","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1016\/S0022-2275(20)31157-3","volume":"42","author":"Du H","year":"2001","journal-title":"J Lipid Res"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1089\/104303402760128586"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/10.16.1639"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1006\/mgme.1998.2707"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2015.00003"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2005-0737"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1016\/j.yexcr.2011.06.016"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1404271111"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1002\/oby.21003"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1016\/j.ceca.2007.04.003"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1194\/jlr.M034876"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(91)90614-5"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1016\/j.atherosclerosis.2012.09.037"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2012.11.005"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1152\/ajpendo.90555.2008"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1016\/0006-2944(84)90037-1"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1136\/adc.44.235.331"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1194\/jlr.D700041-JLR200"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1001\/jama.281.3.249"},{"key":"B32","doi-asserted-by":"crossref","first-page":"2212","DOI":"10.1016\/S0022-2275(20)39205-1","volume":"36","author":"Nakagawa H","year":"1995","journal-title":"J Lipid Res"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1577-09.2009"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1084\/jem.172.1.7"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1189\/jlb.0610318"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1152\/ajpgi.2000.278.3.G354"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1126\/science.1254790"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.2337\/diabetes.50.10.2199"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.3181\/0710-MR-287"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2199-7-21"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-3495(03)70027-7"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbamem.2012.11.013"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1016\/j.bpg.2010.09.001"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1038\/356314a0"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.0000243978.15182.c1"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.2353\/ajpath.2006.051327"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.4238\/2015.October.29.26"}],"container-title":["American Journal of Physiology-Gastrointestinal and Liver Physiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.physiology.org\/doi\/pdf\/10.1152\/ajpgi.00313.2015","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,7,9]],"date-time":"2022-07-09T01:44:35Z","timestamp":1657331075000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.physiology.org\/doi\/10.1152\/ajpgi.00313.2015"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,11,1]]},"references-count":47,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2016,11,1]]}},"alternative-id":["10.1152\/ajpgi.00313.2015"],"URL":"https:\/\/doi.org\/10.1152\/ajpgi.00313.2015","relation":{},"ISSN":["0193-1857","1522-1547"],"issn-type":[{"type":"print","value":"0193-1857"},{"type":"electronic","value":"1522-1547"}],"subject":[],"published":{"date-parts":[[2016,11,1]]}}}