{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T14:20:45Z","timestamp":1791555645989,"version":"4.3.4"},"reference-count":28,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2018,5,5]],"date-time":"2018-05-05T00:00:00Z","timestamp":1525478400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Aging Cell"],"published-print":{"date-parts":[[2018,8]]},"abstract":"<jats:title>Summary<\/jats:title><jats:p>High\u2010temperature requirement protein A1 (<jats:styled-content style=\"fixed-case\">HTRA<\/jats:styled-content>1) is a serine protease secreted by a number of tissues including retinal pigment epithelium (<jats:styled-content style=\"fixed-case\">RPE<\/jats:styled-content>). A promoter variant of the gene encoding <jats:styled-content style=\"fixed-case\">HTRA<\/jats:styled-content>1 is part of a mutant allele that causes increased <jats:styled-content style=\"fixed-case\">HTRA<\/jats:styled-content>1 expression and contributed to age\u2010related macular degeneration (<jats:styled-content style=\"fixed-case\">AMD<\/jats:styled-content>) in genomewide association studies. <jats:styled-content style=\"fixed-case\">AMD<\/jats:styled-content> is characterized by pathological development of drusen, extracellular deposits of proteins and lipids on the basal side of <jats:styled-content style=\"fixed-case\">RPE<\/jats:styled-content>. The molecular pathogenesis of <jats:styled-content style=\"fixed-case\">AMD<\/jats:styled-content> is not well understood, and understanding dysregulation of the extracellular matrix may be key. We assess the high\u2010risk genotype at 10q26 by proteomic comparison of protein levels of <jats:styled-content style=\"fixed-case\">RPE<\/jats:styled-content> cells with and without the mutation. We show <jats:styled-content style=\"fixed-case\">HTRA<\/jats:styled-content>1 protein level is increased in high\u2010risk <jats:styled-content style=\"fixed-case\">RPE<\/jats:styled-content> cells along with several extracellular matrix proteins, including known <jats:styled-content style=\"fixed-case\">HTRA<\/jats:styled-content>1 cleavage targets <jats:styled-content style=\"fixed-case\">LTBP<\/jats:styled-content>\u20101 and clusterin. In addition, two novel targets of <jats:styled-content style=\"fixed-case\">HTRA<\/jats:styled-content>1 have been identified: <jats:styled-content style=\"fixed-case\">EFEMP<\/jats:styled-content>1, an extracellular matrix protein mutated in Doyne honeycomb retinal dystrophy, a genetic eye disease similar to <jats:styled-content style=\"fixed-case\">AMD<\/jats:styled-content>, and thrombospondin 1 (<jats:styled-content style=\"fixed-case\">TSP<\/jats:styled-content>1), an inhibitor of angiogenesis. Our data support the role of <jats:styled-content style=\"fixed-case\">RPE<\/jats:styled-content> extracellular deposition with potential effects in compromised barrier to neovascularization in exudative <jats:styled-content style=\"fixed-case\">AMD<\/jats:styled-content>.<\/jats:p>","DOI":"10.1111\/acel.12710","type":"journal-article","created":{"date-parts":[[2018,5,6]],"date-time":"2018-05-06T04:09:28Z","timestamp":1525579768000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":97,"title":["<scp>HTRA<\/scp>1, an age\u2010related macular degeneration protease, processes extracellular matrix proteins <scp>EFEMP<\/scp>1 and <scp>TSP<\/scp>1"],"prefix":"10.1111","volume":"17","author":[{"given":"Michael K.","family":"Lin","sequence":"first","affiliation":[{"name":"College of Physicians &amp; Surgeons Columbia University New York NY USA"},{"name":"Edward S. Harkness Eye Institute New York\u2010Presbyterian Hospital New York NY USA"},{"name":"Jonas Children's Vision Care, and Bernard &amp; Shirlee Brown Glaucoma Laboratory Columbia Stem Cell Initiative Departments of Ophthalmology, Pathology &amp; Cell Biology Institute of Human Nutrition Herbert Irving Comprehensive Cancer Center Columbia University New York NY USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin","family":"Yang","sequence":"additional","affiliation":[{"name":"Edward S. Harkness Eye Institute New York\u2010Presbyterian Hospital New York NY USA"},{"name":"Jonas Children's Vision Care, and Bernard &amp; Shirlee Brown Glaucoma Laboratory Columbia Stem Cell Initiative Departments of Ophthalmology, Pathology &amp; Cell Biology Institute of Human Nutrition Herbert Irving Comprehensive Cancer Center Columbia University New York NY USA"},{"name":"Tianjin Medical University Eye Hospital Tianjin China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chun Wei","family":"Hsu","sequence":"additional","affiliation":[{"name":"Edward S. Harkness Eye Institute New York\u2010Presbyterian Hospital New York NY USA"},{"name":"Jonas Children's Vision Care, and Bernard &amp; Shirlee Brown Glaucoma Laboratory Columbia Stem Cell Initiative Departments of Ophthalmology, Pathology &amp; Cell Biology Institute of Human Nutrition Herbert Irving Comprehensive Cancer Center Columbia University New York NY USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anuradha","family":"Gore","sequence":"additional","affiliation":[{"name":"Omics Laboratory Department of Ophthalmology Byers Eye Institute Stanford University Palo Alto CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander G.","family":"Bassuk","sequence":"additional","affiliation":[{"name":"Department of Pediatrics and Neurology University of Iowa Iowa City IA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lewis M.","family":"Brown","sequence":"additional","affiliation":[{"name":"Quantitative Proteomics and Metabolomics Center Department of Biological Sciences Columbia University New York NY USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryan","family":"Colligan","sequence":"additional","affiliation":[{"name":"Quantitative Proteomics and Metabolomics Center Department of Biological Sciences Columbia University New York NY USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jesse D.","family":"Sengillo","sequence":"additional","affiliation":[{"name":"Edward S. Harkness Eye Institute New York\u2010Presbyterian Hospital New York NY USA"},{"name":"Jonas Children's Vision Care, and Bernard &amp; Shirlee Brown Glaucoma Laboratory Columbia Stem Cell Initiative Departments of Ophthalmology, Pathology &amp; Cell Biology Institute of Human Nutrition Herbert Irving Comprehensive Cancer Center Columbia University New York NY USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vinit B.","family":"Mahajan","sequence":"additional","affiliation":[{"name":"Omics Laboratory Department of Ophthalmology Byers Eye Institute Stanford University Palo Alto CA USA"},{"name":"Palo Alto Veterans Administration Palo Alto CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen H.","family":"Tsang","sequence":"additional","affiliation":[{"name":"Edward S. Harkness Eye Institute New York\u2010Presbyterian Hospital New York NY USA"},{"name":"Jonas Children's Vision Care, and Bernard &amp; Shirlee Brown Glaucoma Laboratory Columbia Stem Cell Initiative Departments of Ophthalmology, Pathology &amp; Cell Biology Institute of Human Nutrition Herbert Irving Comprehensive Cancer Center Columbia University New York NY USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2018,5,5]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/nri3459"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1418087111"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1207271"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.222551899"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1110189"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddm198"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0501823102"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M500361200"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0501536102"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1110359"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa0801560"},{"key":"e_1_2_7_13_1","first-page":"193","article-title":"HTRA1 overexpression induces the exudative form of age\u2010related macular degeneration","volume":"10","author":"Iejima D.","year":"2015","journal-title":"Journal of Stem Cells"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1102853108"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1109557"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.2119\/molmed.2012.00242"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddq341"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pmed.0030005"},{"key":"e_1_2_7_19_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddm199"},{"key":"e_1_2_7_20_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.202491599"},{"key":"e_1_2_7_21_1","doi-asserted-by":"publisher","DOI":"10.1002\/dvdy.20999"},{"key":"e_1_2_7_22_1","doi-asserted-by":"publisher","DOI":"10.1242\/dev.00999"},{"key":"e_1_2_7_23_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddi353"},{"key":"e_1_2_7_24_1","doi-asserted-by":"publisher","DOI":"10.1001\/archopht.125.1.55"},{"key":"e_1_2_7_25_1","doi-asserted-by":"publisher","DOI":"10.1038\/9722"},{"key":"e_1_2_7_26_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0022959"},{"key":"e_1_2_7_27_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0010329"},{"key":"e_1_2_7_28_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1133811"},{"key":"e_1_2_7_29_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddu053"}],"container-title":["Aging Cell"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1111%2Facel.12710","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/acel.12710","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,18]],"date-time":"2023-09-18T02:13:07Z","timestamp":1695003187000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/acel.12710"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,5,5]]},"references-count":28,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2018,8]]}},"alternative-id":["10.1111\/acel.12710"],"URL":"https:\/\/doi.org\/10.1111\/acel.12710","archive":["Portico"],"relation":{},"ISSN":["1474-9718","1474-9726"],"issn-type":[{"value":"1474-9718","type":"print"},{"value":"1474-9726","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,5,5]]},"assertion":[{"value":"2017-11-07","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2018-05-05","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e12710"}}