Adeno-Associated Viral Vector-Mediated mTOR Inhibition by Short Hairpin RNA Suppresses Laser-Induced Choroidal Neovascularization.
Identifieur interne : 000931 ( Main/Exploration ); précédent : 000930; suivant : 000932Adeno-Associated Viral Vector-Mediated mTOR Inhibition by Short Hairpin RNA Suppresses Laser-Induced Choroidal Neovascularization.
Auteurs : Tae Kwann Park [Corée du Sud] ; Si Hyung Lee [Corée du Sud] ; Jun Sub Choi [Corée du Sud] ; Seung Kwan Nah [Corée du Sud] ; Hee Jong Kim [Corée du Sud] ; Ha Yan Park [Corée du Sud] ; Heuiran Lee [Corée du Sud] ; Steven Hyun Seung Lee [Corée du Sud] ; Keerang Park [Corée du Sud]Source :
- Molecular therapy. Nucleic acids [ 2162-2531 ] ; 2017.
Abstract
Choroidal neovascularization (CNV) is the defining characteristic feature of the wet subtype of age-related macular degeneration (AMD) and may result in irreversible blindness. Based on anti-vascular endothelial growth factor (anti-VEGF), the current therapeutic approaches to CNV are fraught with difficulties, and mammalian target of rapamycin (mTOR) has recently been proposed as a possible therapeutic target, although few studies have been conducted. Here, we show that a recombinant adeno-associated virus-delivered mTOR-inhibiting short hairpin RNA (rAAV-mTOR shRNA), which blocks the activity of both mTOR complex 1 and 2, represents a promising therapeutic approach for the treatment of CNV. Eight-week-old male C57/B6 mice were treated with the short hairpin RNA (shRNA) after generating CNV lesions in the eyes via laser photocoagulation. The recombinant adeno-associated virus (rAAV) delivery vehicle was able to effectively transduce cells in the inner retina, and significantly fewer inflammatory cells and less extensive CNV were observed in the animals treated with rAAV-mTOR shRNA when compared with control- and rAAV-scrambled shRNA-treated groups. Presumably related to the reduction of CNV, increased autophagy was detected in CNV lesions treated with rAAV-mTOR shRNA, whereas significantly fewer apoptotic cells detected in the outer nuclear layer around the CNV indicate that mTOR inhibition may also have neuroprotective effects. Taken together, these results demonstrate the therapeutic potential of mTOR inhibition, resulting from rAAV-mTOR shRNA activity, in the treatment of AMD-related CNV.
DOI: 10.1016/j.omtn.2017.05.012
PubMed: 28918027
PubMed Central: PMC5477068
Affiliations:
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Department of Ophthalmology, Soonchunhyang University Hospital Bucheon, Bucheon 14584, Republic of Korea.</nlm:affiliation><country xml:lang="fr">Corée du Sud</country><wicri:regionArea>Department of Ophthalmology, Soonchunhyang University, College of Medicine, Cheonan 31151, Republic of Korea; Department of Ophthalmology, Soonchunhyang University Hospital Bucheon, Bucheon 14584</wicri:regionArea><wicri:noRegion>Bucheon 14584</wicri:noRegion></affiliation></author><author><name sortKey="Kim, Hee Jong" sort="Kim, Hee Jong" uniqKey="Kim H" first="Hee Jong" last="Kim">Hee Jong Kim</name><affiliation wicri:level="1"><nlm:affiliation>Cdmogen Co., Ltd., Cheongju 28751, Republic of Korea.</nlm:affiliation><country xml:lang="fr">Corée du Sud</country><wicri:regionArea>Cdmogen Co., Ltd., Cheongju 28751</wicri:regionArea><wicri:noRegion>Cheongju 28751</wicri:noRegion></affiliation></author><author><name sortKey="Park, Ha Yan" sort="Park, Ha Yan" uniqKey="Park H" first="Ha Yan" last="Park">Ha Yan Park</name><affiliation wicri:level="1"><nlm:affiliation>Department of Ophthalmology, Soonchunhyang University Hospital Bucheon, Bucheon 14584, Republic of Korea.</nlm:affiliation><country xml:lang="fr">Corée du Sud</country><wicri:regionArea>Department of Ophthalmology, Soonchunhyang University Hospital Bucheon, Bucheon 14584</wicri:regionArea><wicri:noRegion>Bucheon 14584</wicri:noRegion></affiliation></author><author><name sortKey="Lee, Heuiran" sort="Lee, Heuiran" uniqKey="Lee H" first="Heuiran" last="Lee">Heuiran Lee</name><affiliation wicri:level="1"><nlm:affiliation>Department of Microbiology, Cellular Dysfunction Research Center, Asan Medical Center, University of Ulsan, College of Medicine, Seoul 05505, Republic of Korea.</nlm:affiliation><country xml:lang="fr">Corée du Sud</country><wicri:regionArea>Department of Microbiology, Cellular Dysfunction Research Center, Asan Medical Center, University of Ulsan, College of Medicine, Seoul 05505</wicri:regionArea><placeName><settlement type="city">Séoul</settlement><region type="capital">Région capitale de Séoul</region></placeName></affiliation></author><author><name sortKey="Lee, Steven Hyun Seung" sort="Lee, Steven Hyun Seung" uniqKey="Lee S" first="Steven Hyun Seung" last="Lee">Steven Hyun Seung Lee</name><affiliation wicri:level="1"><nlm:affiliation>Department of Microbiology, Cellular Dysfunction Research Center, Asan Medical Center, University of Ulsan, College of Medicine, Seoul 05505, Republic of Korea.</nlm:affiliation><country xml:lang="fr">Corée du Sud</country><wicri:regionArea>Department of Microbiology, Cellular Dysfunction Research Center, Asan Medical Center, University of Ulsan, College of Medicine, Seoul 05505</wicri:regionArea><placeName><settlement type="city">Séoul</settlement><region type="capital">Région capitale de Séoul</region></placeName></affiliation></author><author><name sortKey="Park, Keerang" sort="Park, Keerang" uniqKey="Park K" first="Keerang" last="Park">Keerang Park</name><affiliation wicri:level="1"><nlm:affiliation>Department of Biopharmacy, Chungbuk Health & Science University, Cheongju, Chungbuk 28150, Republic of Korea. 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Electronic address: tkpark@schmc.ac.kr.</nlm:affiliation><country xml:lang="fr">Corée du Sud</country><wicri:regionArea>Department of Ophthalmology, Soonchunhyang University, College of Medicine, Cheonan 31151, Republic of Korea; Department of Ophthalmology, Soonchunhyang University Hospital Bucheon, Bucheon 14584</wicri:regionArea><wicri:noRegion>Bucheon 14584</wicri:noRegion></affiliation></author><author><name sortKey="Lee, Si Hyung" sort="Lee, Si Hyung" uniqKey="Lee S" first="Si Hyung" last="Lee">Si Hyung Lee</name><affiliation wicri:level="1"><nlm:affiliation>Department of Ophthalmology, Soonchunhyang University, College of Medicine, Cheonan 31151, Republic of Korea; Department of Ophthalmology, Soonchunhyang University Hospital Bucheon, Bucheon 14584, Republic of Korea.</nlm:affiliation><country xml:lang="fr">Corée du Sud</country><wicri:regionArea>Department of Ophthalmology, Soonchunhyang University, College of Medicine, Cheonan 31151, Republic of Korea; Department of Ophthalmology, Soonchunhyang University Hospital Bucheon, Bucheon 14584</wicri:regionArea><wicri:noRegion>Bucheon 14584</wicri:noRegion></affiliation></author><author><name sortKey="Choi, Jun Sub" sort="Choi, Jun Sub" uniqKey="Choi J" first="Jun Sub" last="Choi">Jun Sub Choi</name><affiliation wicri:level="1"><nlm:affiliation>Cdmogen Co., Ltd., Cheongju 28751, Republic of Korea.</nlm:affiliation><country xml:lang="fr">Corée du Sud</country><wicri:regionArea>Cdmogen Co., Ltd., Cheongju 28751</wicri:regionArea><wicri:noRegion>Cheongju 28751</wicri:noRegion></affiliation></author><author><name sortKey="Nah, Seung Kwan" sort="Nah, Seung Kwan" uniqKey="Nah S" first="Seung Kwan" last="Nah">Seung Kwan Nah</name><affiliation wicri:level="1"><nlm:affiliation>Department of Ophthalmology, Soonchunhyang University, College of Medicine, Cheonan 31151, Republic of Korea; Department of Ophthalmology, Soonchunhyang University Hospital Bucheon, Bucheon 14584, Republic of Korea.</nlm:affiliation><country xml:lang="fr">Corée du Sud</country><wicri:regionArea>Department of Ophthalmology, Soonchunhyang University, College of Medicine, Cheonan 31151, Republic of Korea; Department of Ophthalmology, Soonchunhyang University Hospital Bucheon, Bucheon 14584</wicri:regionArea><wicri:noRegion>Bucheon 14584</wicri:noRegion></affiliation></author><author><name sortKey="Kim, Hee Jong" sort="Kim, Hee Jong" uniqKey="Kim H" first="Hee Jong" last="Kim">Hee Jong Kim</name><affiliation wicri:level="1"><nlm:affiliation>Cdmogen Co., Ltd., Cheongju 28751, Republic of Korea.</nlm:affiliation><country xml:lang="fr">Corée du Sud</country><wicri:regionArea>Cdmogen Co., Ltd., Cheongju 28751</wicri:regionArea><wicri:noRegion>Cheongju 28751</wicri:noRegion></affiliation></author><author><name sortKey="Park, Ha Yan" sort="Park, Ha Yan" uniqKey="Park H" first="Ha Yan" last="Park">Ha Yan Park</name><affiliation wicri:level="1"><nlm:affiliation>Department of Ophthalmology, Soonchunhyang University Hospital Bucheon, Bucheon 14584, Republic of Korea.</nlm:affiliation><country xml:lang="fr">Corée du Sud</country><wicri:regionArea>Department of Ophthalmology, Soonchunhyang University Hospital Bucheon, Bucheon 14584</wicri:regionArea><wicri:noRegion>Bucheon 14584</wicri:noRegion></affiliation></author><author><name sortKey="Lee, Heuiran" sort="Lee, Heuiran" uniqKey="Lee H" first="Heuiran" last="Lee">Heuiran Lee</name><affiliation wicri:level="1"><nlm:affiliation>Department of Microbiology, Cellular Dysfunction Research Center, Asan Medical Center, University of Ulsan, College of Medicine, Seoul 05505, Republic of Korea.</nlm:affiliation><country xml:lang="fr">Corée du Sud</country><wicri:regionArea>Department of Microbiology, Cellular Dysfunction Research Center, Asan Medical Center, University of Ulsan, College of Medicine, Seoul 05505</wicri:regionArea><placeName><settlement type="city">Séoul</settlement><region type="capital">Région capitale de Séoul</region></placeName></affiliation></author><author><name sortKey="Lee, Steven Hyun Seung" sort="Lee, Steven Hyun Seung" uniqKey="Lee S" first="Steven Hyun Seung" last="Lee">Steven Hyun Seung Lee</name><affiliation wicri:level="1"><nlm:affiliation>Department of Microbiology, Cellular Dysfunction Research Center, Asan Medical Center, University of Ulsan, College of Medicine, Seoul 05505, Republic of Korea.</nlm:affiliation><country xml:lang="fr">Corée du Sud</country><wicri:regionArea>Department of Microbiology, Cellular Dysfunction Research Center, Asan Medical Center, University of Ulsan, College of Medicine, Seoul 05505</wicri:regionArea><placeName><settlement type="city">Séoul</settlement><region type="capital">Région capitale de Séoul</region></placeName></affiliation></author><author><name sortKey="Park, Keerang" sort="Park, Keerang" uniqKey="Park K" first="Keerang" last="Park">Keerang Park</name><affiliation wicri:level="1"><nlm:affiliation>Department of Biopharmacy, Chungbuk Health & Science University, Cheongju, Chungbuk 28150, Republic of Korea. Electronic address: krpark@chsu.ac.kr.</nlm:affiliation><country xml:lang="fr">Corée du Sud</country><wicri:regionArea>Department of Biopharmacy, Chungbuk Health & Science University, Cheongju, Chungbuk 28150</wicri:regionArea><wicri:noRegion>Chungbuk 28150</wicri:noRegion></affiliation></author></analytic><series><title level="j">Molecular therapy. Nucleic acids</title><idno type="ISSN">2162-2531</idno><imprint><date when="2017" type="published">2017</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Choroidal neovascularization (CNV) is the defining characteristic feature of the wet subtype of age-related macular degeneration (AMD) and may result in irreversible blindness. Based on anti-vascular endothelial growth factor (anti-VEGF), the current therapeutic approaches to CNV are fraught with difficulties, and mammalian target of rapamycin (mTOR) has recently been proposed as a possible therapeutic target, although few studies have been conducted. Here, we show that a recombinant adeno-associated virus-delivered mTOR-inhibiting short hairpin RNA (rAAV-mTOR shRNA), which blocks the activity of both mTOR complex 1 and 2, represents a promising therapeutic approach for the treatment of CNV. Eight-week-old male C57/B6 mice were treated with the short hairpin RNA (shRNA) after generating CNV lesions in the eyes via laser photocoagulation. The recombinant adeno-associated virus (rAAV) delivery vehicle was able to effectively transduce cells in the inner retina, and significantly fewer inflammatory cells and less extensive CNV were observed in the animals treated with rAAV-mTOR shRNA when compared with control- and rAAV-scrambled shRNA-treated groups. Presumably related to the reduction of CNV, increased autophagy was detected in CNV lesions treated with rAAV-mTOR shRNA, whereas significantly fewer apoptotic cells detected in the outer nuclear layer around the CNV indicate that mTOR inhibition may also have neuroprotective effects. Taken together, these results demonstrate the therapeutic potential of mTOR inhibition, resulting from rAAV-mTOR shRNA activity, in the treatment of AMD-related CNV.</div></front></TEI><pubmed><MedlineCitation Status="PubMed-not-MEDLINE" Owner="NLM"><PMID Version="1">28918027</PMID><DateRevised><Year>2020</Year><Month>09</Month><Day>28</Day></DateRevised><Article PubModel="Print-Electronic"><Journal><ISSN IssnType="Print">2162-2531</ISSN><JournalIssue CitedMedium="Print"><Volume>8</Volume><PubDate><Year>2017</Year><Month>Sep</Month><Day>15</Day></PubDate></JournalIssue><Title>Molecular therapy. Nucleic acids</Title><ISOAbbreviation>Mol Ther Nucleic Acids</ISOAbbreviation></Journal><ArticleTitle>Adeno-Associated Viral Vector-Mediated mTOR Inhibition by Short Hairpin RNA Suppresses Laser-Induced Choroidal Neovascularization.</ArticleTitle><Pagination><MedlinePgn>26-35</MedlinePgn></Pagination><ELocationID EIdType="pii" ValidYN="Y">S2162-2531(17)30183-X</ELocationID><ELocationID EIdType="doi" ValidYN="Y">10.1016/j.omtn.2017.05.012</ELocationID><Abstract><AbstractText>Choroidal neovascularization (CNV) is the defining characteristic feature of the wet subtype of age-related macular degeneration (AMD) and may result in irreversible blindness. Based on anti-vascular endothelial growth factor (anti-VEGF), the current therapeutic approaches to CNV are fraught with difficulties, and mammalian target of rapamycin (mTOR) has recently been proposed as a possible therapeutic target, although few studies have been conducted. Here, we show that a recombinant adeno-associated virus-delivered mTOR-inhibiting short hairpin RNA (rAAV-mTOR shRNA), which blocks the activity of both mTOR complex 1 and 2, represents a promising therapeutic approach for the treatment of CNV. Eight-week-old male C57/B6 mice were treated with the short hairpin RNA (shRNA) after generating CNV lesions in the eyes via laser photocoagulation. The recombinant adeno-associated virus (rAAV) delivery vehicle was able to effectively transduce cells in the inner retina, and significantly fewer inflammatory cells and less extensive CNV were observed in the animals treated with rAAV-mTOR shRNA when compared with control- and rAAV-scrambled shRNA-treated groups. Presumably related to the reduction of CNV, increased autophagy was detected in CNV lesions treated with rAAV-mTOR shRNA, whereas significantly fewer apoptotic cells detected in the outer nuclear layer around the CNV indicate that mTOR inhibition may also have neuroprotective effects. Taken together, these results demonstrate the therapeutic potential of mTOR inhibition, resulting from rAAV-mTOR shRNA activity, in the treatment of AMD-related CNV.</AbstractText><CopyrightInformation>Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.</CopyrightInformation></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Park</LastName><ForeName>Tae Kwann</ForeName><Initials>TK</Initials><AffiliationInfo><Affiliation>Department of Ophthalmology, Soonchunhyang University, College of Medicine, Cheonan 31151, Republic of Korea; Department of Ophthalmology, Soonchunhyang University Hospital Bucheon, Bucheon 14584, Republic of Korea. Electronic address: tkpark@schmc.ac.kr.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Lee</LastName><ForeName>Si Hyung</ForeName><Initials>SH</Initials><AffiliationInfo><Affiliation>Department of Ophthalmology, Soonchunhyang University, College of Medicine, Cheonan 31151, Republic of Korea; Department of Ophthalmology, Soonchunhyang University Hospital Bucheon, Bucheon 14584, Republic of Korea.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Choi</LastName><ForeName>Jun Sub</ForeName><Initials>JS</Initials><AffiliationInfo><Affiliation>Cdmogen Co., Ltd., Cheongju 28751, Republic of Korea.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Nah</LastName><ForeName>Seung Kwan</ForeName><Initials>SK</Initials><AffiliationInfo><Affiliation>Department of Ophthalmology, Soonchunhyang University, College of Medicine, Cheonan 31151, Republic of Korea; Department of Ophthalmology, Soonchunhyang University Hospital Bucheon, Bucheon 14584, Republic of Korea.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Kim</LastName><ForeName>Hee Jong</ForeName><Initials>HJ</Initials><AffiliationInfo><Affiliation>Cdmogen Co., Ltd., Cheongju 28751, Republic of Korea.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Park</LastName><ForeName>Ha Yan</ForeName><Initials>HY</Initials><AffiliationInfo><Affiliation>Department of Ophthalmology, Soonchunhyang University Hospital Bucheon, Bucheon 14584, Republic of Korea.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Lee</LastName><ForeName>Heuiran</ForeName><Initials>H</Initials><AffiliationInfo><Affiliation>Department of Microbiology, Cellular Dysfunction Research Center, Asan Medical Center, University of Ulsan, College of Medicine, Seoul 05505, Republic of Korea.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Lee</LastName><ForeName>Steven Hyun Seung</ForeName><Initials>SHS</Initials><AffiliationInfo><Affiliation>Department of Microbiology, Cellular Dysfunction Research Center, Asan Medical Center, University of Ulsan, College of Medicine, Seoul 05505, Republic of Korea.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Park</LastName><ForeName>Keerang</ForeName><Initials>K</Initials><AffiliationInfo><Affiliation>Department of Biopharmacy, Chungbuk Health & Science University, Cheongju, Chungbuk 28150, Republic of Korea. Electronic address: krpark@chsu.ac.kr.</Affiliation></AffiliationInfo></Author></AuthorList><Language>eng</Language><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType></PublicationTypeList><ArticleDate DateType="Electronic"><Year>2017</Year><Month>06</Month><Day>01</Day></ArticleDate></Article><MedlineJournalInfo><Country>United States</Country><MedlineTA>Mol Ther Nucleic Acids</MedlineTA><NlmUniqueID>101581621</NlmUniqueID><ISSNLinking>2162-2531</ISSNLinking></MedlineJournalInfo><KeywordList Owner="NOTNLM"><Keyword MajorTopicYN="N">RNA interference</Keyword><Keyword MajorTopicYN="N">adeno-associated virus</Keyword><Keyword MajorTopicYN="N">autophagy</Keyword><Keyword MajorTopicYN="N">choroidal neovascularization</Keyword><Keyword MajorTopicYN="N">mTOR</Keyword><Keyword MajorTopicYN="N">mTOR shRNA</Keyword><Keyword MajorTopicYN="N">retinal neovascularization</Keyword></KeywordList></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="received"><Year>2017</Year><Month>02</Month><Day>08</Day></PubMedPubDate><PubMedPubDate PubStatus="revised"><Year>2017</Year><Month>05</Month><Day>29</Day></PubMedPubDate><PubMedPubDate PubStatus="accepted"><Year>2017</Year><Month>05</Month><Day>29</Day></PubMedPubDate><PubMedPubDate PubStatus="entrez"><Year>2017</Year><Month>9</Month><Day>18</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="pubmed"><Year>2017</Year><Month>9</Month><Day>18</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2017</Year><Month>9</Month><Day>18</Day><Hour>6</Hour><Minute>1</Minute></PubMedPubDate></History><PublicationStatus>ppublish</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">28918027</ArticleId><ArticleId IdType="pii">S2162-2531(17)30183-X</ArticleId><ArticleId IdType="doi">10.1016/j.omtn.2017.05.012</ArticleId><ArticleId IdType="pmc">PMC5477068</ArticleId></ArticleIdList></PubmedData></pubmed><affiliations><list><country><li>Corée du Sud</li></country><region><li>Région capitale de Séoul</li></region><settlement><li>Séoul</li></settlement></list><tree><country name="Corée du Sud"><noRegion><name sortKey="Park, Tae Kwann" sort="Park, Tae Kwann" uniqKey="Park T" first="Tae Kwann" last="Park">Tae Kwann Park</name></noRegion><name sortKey="Choi, Jun Sub" sort="Choi, Jun Sub" uniqKey="Choi J" first="Jun Sub" last="Choi">Jun Sub Choi</name><name sortKey="Kim, Hee Jong" sort="Kim, Hee Jong" uniqKey="Kim H" first="Hee Jong" last="Kim">Hee Jong Kim</name><name sortKey="Lee, Heuiran" sort="Lee, Heuiran" uniqKey="Lee H" first="Heuiran" last="Lee">Heuiran Lee</name><name sortKey="Lee, Si Hyung" sort="Lee, Si Hyung" uniqKey="Lee S" first="Si Hyung" last="Lee">Si Hyung Lee</name><name sortKey="Lee, Steven Hyun Seung" sort="Lee, Steven Hyun Seung" uniqKey="Lee S" first="Steven Hyun Seung" last="Lee">Steven Hyun Seung Lee</name><name sortKey="Nah, Seung Kwan" sort="Nah, Seung Kwan" uniqKey="Nah S" first="Seung Kwan" last="Nah">Seung Kwan Nah</name><name sortKey="Park, Ha Yan" sort="Park, Ha Yan" uniqKey="Park H" first="Ha Yan" last="Park">Ha Yan Park</name><name sortKey="Park, Keerang" sort="Park, Keerang" uniqKey="Park K" first="Keerang" last="Park">Keerang Park</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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