A Neuroprotective Locus Modulates Ischemic Stroke Infarction Independent of Collateral Vessel Anatomy.
A Neuroprotective Locus Modulates Ischemic Stroke Infarction Independent of Collateral Vessel Anatomy.
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DOI：
10.3389/fnins.2021.705160
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发表时间：
2021
影响因子：
4.3
通讯作者：
Marchuk DA
中科院分区：
文献类型：
--
作者：
Lee HK;Wetzel-Strong SE;Aylor DL;Marchuk DA
尽管对近交系小鼠的研究表明，梗死面积在很大程度上取决于脑中动脉之间的侧支血管连接的程度，这些血管连接使缺血区域能够再灌注，但我们已经确定了在这种血管表型上没有变化的品系对，但它们在梗死面积上表现出很大的差异。在这项研究中，我们进行了数量性状基因座（QTL）定位在两个这样的品系，WSB/EiJ（WSB）和C57 BL/6 J（B6）之间的互交小鼠。该QTL定位揭示了8号染色体（Chr 8）上仅一个神经保护位点，其与我们先前从C3 H/HeJ（C3 H）和B6之间的F2后代中定位的神经保护位点共定位。这两个独立的映射确定的基因区域的梗死体积的等位基因特异性表型效应是在相反的方向的亲本菌株表型，即，B6等位基因赋予缺血性梗死的易感性增加。通过两个相互同源的小鼠品系，无论是C3 H或B6背景的Chr 8基因座，我们验证了神经保护作用的遗传区域，调制梗死体积没有任何影响的侧支血管。此外，我们调查了非同义编码SNP，并进行RNA测序分析，以确定潜在的候选基因的遗传区间内。通过这些方法，我们提出了新的基因，为未来的机制研究梗死后缺血性卒中，这可能代表新的基因/蛋白质靶点的治疗发展。
Although studies with inbred strains of mice have shown that infarct size is largely determined by the extent of collateral vessel connections between arteries in the brain that enable reperfusion of the ischemic territory, we have identified strain pairs that do not vary in this vascular phenotype, but which nonetheless exhibit large differences in infarct size. In this study we performed quantitative trait locus (QTL) mapping in mice from an intercross between two such strains, WSB/EiJ (WSB) and C57BL/6J (B6). This QTL mapping revealed only one neuroprotective locus on Chromosome 8 (Chr 8) that co-localizes with a neuroprotective locus we mapped previously from F2 progeny between C3H/HeJ (C3H) and B6. The allele-specific phenotypic effect on infarct volume at the genetic region identified by these two independent mappings was in the opposite direction of the parental strain phenotype; namely, the B6 allele conferred increased susceptibility to ischemic infarction. Through two reciprocal congenic mouse lines with either the C3H or B6 background at the Chr 8 locus, we verified the neuroprotective effects of this genetic region that modulates infarct volume without any effect on the collateral vasculature. Additionally, we surveyed non-synonymous coding SNPs and performed RNA-sequencing analysis to identify potential candidate genes within the genetic interval. Through these approaches, we suggest new genes for future mechanistic studies of infarction following ischemic stroke, which may represent novel gene/protein targets for therapeutic development.
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DOI：
10.1093/bioinformatics/btu638
发表时间：
2015-01-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Anders S;Pyl PT;Huber W
通讯作者：
Huber W
影响因子：
30.8
作者：
Malik R;Chauhan G;Traylor M;Sargurupremraj M;Okada Y;Mishra A;Rutten-Jacobs L;Giese AK;van der Laan SW;Gretarsdottir S;Anderson CD;Chong M;Adams HHH;Ago T;Almgren P;Amouyel P;Ay H;Bartz TM;Benavente OR;Bevan S;Boncoraglio GB;Brown RD Jr;Butterworth AS;Carrera C;Carty CL;Chasman DI;Chen WM;Cole JW;Correa A;Cotlarciuc I;Cruchaga C;Danesh J;de Bakker PIW;DeStefano AL;den Hoed M;Duan Q;Engelter ST;Falcone GJ;Gottesman RF;Grewal RP;Gudnason V;Gustafsson S;Haessler J;Harris TB;Hassan A;Havulinna AS;Heckbert SR;Holliday EG;Howard G;Hsu FC;Hyacinth HI;Ikram MA;Ingelsson E;Irvin MR;Jian X;Jiménez-Conde J;Johnson JA;Jukema JW;Kanai M;Keene KL;Kissela BM;Kleindorfer DO;Kooperberg C;Kubo M;Lange LA;Langefeld CD;Langenberg C;Launer LJ;Lee JM;Lemmens R;Leys D;Lewis CM;Lin WY;Lindgren AG;Lorentzen E;Magnusson PK;Maguire J;Manichaikul A;McArdle PF;Meschia JF;Mitchell BD;Mosley TH;Nalls MA;Ninomiya T;O'Donnell MJ;Psaty BM;Pulit SL;Rannikmäe K;Reiner AP;Rexrode KM;Rice K;Rich SS;Ridker PM;Rost NS;Rothwell PM;Rotter JI;Rundek T;Sacco RL;Sakaue S;Sale MM;Salomaa V;Sapkota BR;Schmidt R;Schmidt CO;Schminke U;Sharma P;Slowik A;Sudlow CLM;Tanislav C;Tatlisumak T;Taylor KD;Thijs VNS;Thorleifsson G;Thorsteinsdottir U;Tiedt S;Trompet S;Tzourio C;van Duijn CM;Walters M;Wareham NJ;Wassertheil-Smoller S;Wilson JG;Wiggins KL;Yang Q;Yusuf S;AFGen Consortium;Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium;International Genomics of Blood Pressure (iGEN-BP) Consortium;INVENT Consortium;STARNET;Bis JC;Pastinen T;Ruusalepp A;Schadt EE;Koplev S;Björkegren JLM;Codoni V;Civelek M;Smith NL;Trégouët DA;Christophersen IE;Roselli C;Lubitz SA;Ellinor PT;Tai ES;Kooner JS;Kato N;He J;van der Harst P;Elliott P;Chambers JC;Takeuchi F;Johnson AD;BioBank Japan Cooperative Hospital Group;COMPASS Consortium;EPIC-CVD Consortium;EPIC-InterAct Consortium;International Stroke Genetics Consortium (ISGC);METASTROKE Consortium;Neurology Working Group of the CHARGE Consortium;NINDS Stroke Genetics Network (SiGN);UK Young Lacunar DNA Study;MEGASTROKE Consortium;Sanghera DK;Melander O;Jern C;Strbian D;Fernandez-Cadenas I;Longstreth WT Jr;Rolfs A;Hata J;Woo D;Rosand J;Pare G;Hopewell JC;Saleheen D;Stefansson K;Worrall BB;Kittner SJ;Seshadri S;Fornage M;Markus HS;Howson JMM;Kamatani Y;Debette S;Dichgans M
通讯作者：
Dichgans M
影响因子：
4.5
作者：
Keum S;Lee HK;Chu PL;Kan MJ;Huang MN;Gallione CJ;Gunn MD;Lo DC;Marchuk DA
通讯作者：
Marchuk DA
影响因子：
15.9
作者：
Lee, Han Kyu;Keum, Sehoon;Marchuk, Douglas A.
通讯作者：
Marchuk, Douglas A.
DOI：
10.1111/j.2517-6161.1995.tb02031.x
发表时间：
1995-01-01
影响因子：
5.8
作者：
BENJAMINI, Y;HOCHBERG, Y
通讯作者：
HOCHBERG, Y