A Genome-Wide Analysis of the Penumbral Volume in Inbred Mice Following Middle Cerebral Artery Occlusion

Overview

Journal Sci Rep

Specialty Science

Date 2019 Mar 27

PMID 30911049

Citations 3

Authors

Robert F Rudy

Nareerat Charoenvimolphan

Baogang Qian

Annerose Berndt

Robert M Friedlander

Scott T Weiss

Rose Du

Affiliations

Soon will be listed here.

Abstract

Following ischemic stroke, the penumbra, at-risk neural tissue surrounding the core infarct, survives for a variable period of time before progressing to infarction. We investigated genetic determinants of the size of penumbra in mice subjected to middle cerebral artery occlusion (MCAO) using a genome-wide approach. 449 male mice from 33 inbred strains underwent MCAO for 6 hours (215 mice) or 24 hours (234 mice). A genome-wide association study using genetic data from the Mouse HapMap project was performed to examine the effects of genetic variants on the penumbra ratio, defined as the ratio of the infarct volume after 6 hours to the infarct volume after 24 hours of MCAO. Efficient mixed model analysis was used to account for strain interrelatedness. Penumbra ratio differed significantly by strain (F = 2.7, P < 0.001) and was associated with 18 significant SNPs, including 6 protein coding genes. We have identified 6 candidate genes for penumbra ratio: Clint1, Nbea, Smtnl2, Rin3, Dclk1, and Slc24a4.

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References

Swanson R, Sharp F . Infarct measurement methodology. J Cereb Blood Flow Metab. 1994; 14(4):697-8. DOI: 10.1038/jcbfm.1994.88. View

Wang J, Duncan D, Shi Z, Zhang B . WEB-based GEne SeT AnaLysis Toolkit (WebGestalt): update 2013. Nucleic Acids Res. 2013; 41(Web Server issue):W77-83. PMC: 3692109. DOI: 10.1093/nar/gkt439. View

Zheng L, Cheng W, Wang X, Yang Z, Zhou X, Pan C . Overexpression of MicroRNA-145 Ameliorates Astrocyte Injury by Targeting Aquaporin 4 in Cerebral Ischemic Stroke. Biomed Res Int. 2017; 2017:9530951. PMC: 5615955. DOI: 10.1155/2017/9530951. View

Petkov P, Ding Y, Cassell M, Zhang W, Wagner G, Sargent E . An efficient SNP system for mouse genome scanning and elucidating strain relationships. Genome Res. 2004; 14(9):1806-11. PMC: 515327. DOI: 10.1101/gr.2825804. View

Casper J, Zweig A, Villarreal C, Tyner C, Speir M, Rosenbloom K . The UCSC Genome Browser database: 2018 update. Nucleic Acids Res. 2017; 46(D1):D762-D769. PMC: 5753355. DOI: 10.1093/nar/gkx1020. View

Kang H, Zaitlen N, Wade C, Kirby A, Heckerman D, Daly M . Efficient control of population structure in model organism association mapping. Genetics. 2008; 178(3):1709-23. PMC: 2278096. DOI: 10.1534/genetics.107.080101. View

Szklarczyk D, Morris J, Cook H, Kuhn M, Wyder S, Simonovic M . The STRING database in 2017: quality-controlled protein-protein association networks, made broadly accessible. Nucleic Acids Res. 2016; 45(D1):D362-D368. PMC: 5210637. DOI: 10.1093/nar/gkw937. View

Jia L, Hao F, Wang W, Qu Y . Circulating miR-145 is associated with plasma high-sensitivity C-reactive protein in acute ischemic stroke patients. Cell Biochem Funct. 2015; 33(5):314-9. DOI: 10.1002/cbf.3116. View

Medrihan L, Rohlmann A, Fairless R, Andrae J, Doring M, Missler M . Neurobeachin, a protein implicated in membrane protein traffic and autism, is required for the formation and functioning of central synapses. J Physiol. 2009; 587(Pt 21):5095-106. PMC: 2790251. DOI: 10.1113/jphysiol.2009.178236. View

10.

Ostenfeld M, Bramsen J, Lamy P, Villadsen S, Fristrup N, Sorensen K . miR-145 induces caspase-dependent and -independent cell death in urothelial cancer cell lines with targeting of an expression signature present in Ta bladder tumors. Oncogene. 2009; 29(7):1073-84. DOI: 10.1038/onc.2009.395. View

11.

Dharap A, Pokrzywa C, Vemuganti R . Increased binding of stroke-induced long non-coding RNAs to the transcriptional corepressors Sin3A and coREST. ASN Neuro. 2013; 5(4):283-9. PMC: 3806319. DOI: 10.1042/AN20130029. View

12.

Durinck S, Spellman P, Birney E, Huber W . Mapping identifiers for the integration of genomic datasets with the R/Bioconductor package biomaRt. Nat Protoc. 2009; 4(8):1184-91. PMC: 3159387. DOI: 10.1038/nprot.2009.97. View

13.

Ovbiagele B, Goldstein L, Higashida R, Howard V, Johnston S, Khavjou O . Forecasting the future of stroke in the United States: a policy statement from the American Heart Association and American Stroke Association. Stroke. 2013; 44(8):2361-75. DOI: 10.1161/STR.0b013e31829734f2. View

14.

Cuomo O, Gala R, Pignataro G, Boscia F, Secondo A, Scorziello A . A critical role for the potassium-dependent sodium-calcium exchanger NCKX2 in protection against focal ischemic brain damage. J Neurosci. 2008; 28(9):2053-63. PMC: 6671846. DOI: 10.1523/JNEUROSCI.4912-07.2008. View

15.

Gordon E, Whisenant T, Zeller M, Kaake R, Gordon W, Krotee P . Combining docking site and phosphosite predictions to find new substrates: identification of smoothelin-like-2 (SMTNL2) as a c-Jun N-terminal kinase (JNK) substrate. Cell Signal. 2013; 25(12):2518-29. PMC: 4132694. DOI: 10.1016/j.cellsig.2013.08.004. View

16.

Zhang H, Prabhakar P, Sealock R, Faber J . Wide genetic variation in the native pial collateral circulation is a major determinant of variation in severity of stroke. J Cereb Blood Flow Metab. 2010; 30(5):923-34. PMC: 2949178. DOI: 10.1038/jcbfm.2010.10. View

17.

Albers G, Marks M, Kemp S, Christensen S, Tsai J, Ortega-Gutierrez S . Thrombectomy for Stroke at 6 to 16 Hours with Selection by Perfusion Imaging. N Engl J Med. 2018; 378(8):708-718. PMC: 6590673. DOI: 10.1056/NEJMoa1713973. View

18.

Hori M, Nakamachi T, Shibato J, Rakwal R, Shioda S, Numazawa S . Unraveling the Specific Ischemic Core and Penumbra Transcriptome in the Permanent Middle Cerebral Artery Occlusion Mouse Model Brain Treated with the Neuropeptide PACAP38. Microarrays (Basel). 2016; 4(1):2-24. PMC: 4996388. DOI: 10.3390/microarrays4010002. View

19.

Lucitti J, Sealock R, Buckley B, Zhang H, Xiao L, Dudley A . Variants of Rab GTPase-Effector Binding Protein-2 Cause Variation in the Collateral Circulation and Severity of Stroke. Stroke. 2016; 47(12):3022-3031. PMC: 5134893. DOI: 10.1161/STROKEAHA.116.014160. View

20.

Romanic A, White R, Arleth A, Ohlstein E, Barone F . Matrix metalloproteinase expression increases after cerebral focal ischemia in rats: inhibition of matrix metalloproteinase-9 reduces infarct size. Stroke. 1998; 29(5):1020-30. DOI: 10.1161/01.str.29.5.1020. View