Contribution of the X Chromosome to Sex Differences in Stroke

X 染色体对中风性别差异的影响

• 批准号: 10406269
• 负责人: Fudong Liu
• 金额: $ 54.6万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-15 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10406269
• 关键词: Affect; Age; Aging; Alleles; Animal Model; Animals; Anti-Inflammatory Agents; Area; Behavior; Behavioral; Brain; Cardiac; Cells; Data; Disease; Dissociation; Elderly; Elderly woman; Epigenetic Process; Estrogens; Experimental Models; Exposure to; Female; Four Core Genotypes; Gene Expression; Gene Silencing; Genes; Genetic; Genotype; Goals; Gonadal Hormones; IRF1 gene; IRF3 gene; Immune response; Incidence; Infarction; Inflammatory; Inflammatory Response; Interferons; Investigation; Ischemia; Ischemic Stroke; Knockout Mice; Longevity; Macrophage Activation; Mediating; Mediation; Microglia; Modification; Molecular; Morbidity - disease rate; Mus; Outcome; Ovariectomy; Ovary; Pathologic; Pathway interactions; Phenotype; Play; Ploidies; Process; Proteins; Public Health; Recovery; Reperfusion Injury; Role; Sex Chromosomes; Sex Differences; Signal Transduction; Stroke; Testing; Testis; Therapeutic; Tissues; Woman; Work; X Chromosome; X Inactivation; Y Chromosome; aged; aging brain; artery occlusion; cerebral artery; conditional knockout; demethylation; dosage; epidemiologic data; histone demethylase; innovation; juvenile animal; knockout animal; male; men; mortality; mouse model; novel; post stroke; response; sex; sexual dimorphism; stroke outcome; stroke victims; transcriptome sequencing

PROJECT SUMMARY The overall goal of this proposal is to determine the sex chromosome genes that regulate ischemic stroke sensitivity in the aged brain, and to explore the mechanisms underlying their regulatory role. It has been increasingly recognized that stroke is a sexually dimorphic disease, however, the mechanisms underlying these sex differences are not known. The elderly constitute the majority of stroke victims, and aged women have a higher incidence, higher morbidity and higher mortality compared to age-matched men, and these differences cannot be explained solely by exposure to gonadal hormones. Previous work has shown the sex chromosome complement contributes to stroke sensitivity selectively in aged animals, when gonadal hormones are equivalent between the sexes. We have found that there is an effect of the X chromosome dosage (one X or XX) on microglial activation and immune responses. A prominent feature of the aged X chromosome is that genetic silencing of genes on the second X chromosome becomes incomplete, allowing for genes to escape from X-chromosome inactivation (XCI). This results in higher expression of these X escapee genes in XX vs. XY cells in many tissues. Kdm6a and Kdm5c are two X escapees that can regulate expression of interferon regulatory factors (IRFs) that are responsible for microglial activation through epigenetic modification. Recent work has found Kdm6a and Kdm5c are more highly expressed in microglia derived from aged female vs. male ischemic brain. Our CENTRAL HYPOTHESIS is that X chromosome complement contributes to stroke sensitivity in the aged brain, AND that the X escapee genes Kdm6a and Kdm5c epigenetically modify IRF1/3/4/5/8 in aged microglia leading to sex-specific inflammatory responses. In Aim 1 we will use the XY* mouse model to determine if the X chromosome contributes to stroke sensitivity in aged animals. Aim 2 will use an inducible conditional knock out (ICKO) animal model to test the hypothesis that Kdm6a and Kdm5c sex specifically impact on stroke outcomes through a mechanism of epigenetic modification, i.e. demethylation of H3K27me3 and H3K4me3 marks respectively. Aim 3 will test the hypothesis that X chromosome and Kdm6a/Kdm5c regulate microglial activation and immune responses through mediation of IRF1/3/4/5/8 expression. These proposed studies will investigate the Kdm6a/5c- H3k27me3/H3K4me3-IRFs signaling axes, a very innovative and novel area. We hypothesize that this pathway plays a critical role in inducing sex differences in stroke in the aged.

项目摘要 该提案的总体目标是确定调节缺血性中风的性染色体基因 老化大脑的敏感性，并探索其调节作用的机制。它一直 然而，越来越认识到中风是一种性二态性疾病 这些性别差异尚不清楚。老年人构成大多数中风受害者，并且老年 与年龄匹配的男性相比 这些差异不能仅通过暴露于性腺激素来解释。以前的工作有 显示性别染色体补体在老年动物中有选择性地促进中风敏感性， 当性腺激素在性别之间等效时。我们发现 X染色体剂量（一个X或XX）在小胶质激活和免疫反应上。一个突出的 老年X染色体的特征是第二个X染色体上基因的遗传沉默 变得不完整，允许基因从X染色体灭活（XCI）中逃脱。这结果 在许多组织中XX与XY细胞中这些X Escape基因的更高表达中。 KDM6A和KDM5C 是两个可以调节干扰素调节因子（IRF）表达的X逃生者 通过表观遗传修饰负责小胶质细胞激活。最近的工作发现了KDM6A和 KDM5C在源自老年雌性和雄性缺血性脑的小胶质细胞中更高表达。我们的 中心假设是X染色体补体有助于衰老的中风灵敏度 大脑，X EscapeE基因KDM6A和KDM5C表观遗传在老年中修改IRF1/3/4/5/8 小胶质细胞导致性别特异性炎症反应。在AIM 1中，我们将使用XY*鼠标模型 确定X染色体是否有助于老年动物的中风灵敏度。 AIM 2将使用 可诱导的条件敲除（ICKO）动物模型，以检验KDM6A和KDM5C性别的假设 通过表观遗传修饰的机制，即，特定影响中风结果的影响，即 H3K27me3和H3K4Me3的去甲基化分别标记。 AIM 3将检验X的假设 染色体和KDM6A/KDM5C通过调解调节小胶质细胞激活和免疫反应 IRF1/3/4/5/8表达的表达。这些提出的研究将研究KDM6A/5C- H3K27ME3/H3K4ME3-IRFS信号轴，一个非常创新且新颖的区域。我们假设这是 途径在诱导老年人中风的性别差异中起着至关重要的作用。

项目成果

Central IRF4/5 Signaling Are Critical for Microglial Activation and Impact on Stroke Outcomes.

• DOI: 10.1007/s12975-023-01172-2
• 发表时间: 2023-07
• 期刊: Translational stroke research
• 影响因子: 6.9
• 作者: Conelius Ngwa;Abdullah Al Mamun;Shaohua Qi;Romana Sharmeen;M. P. B. Conesa;B. Ganesh;B. Manwani;Fudong Liu

X chromosome escapee genes are involved in ischemic sexual dimorphism through epigenetic modification of inflammatory signals.

• DOI: 10.1186/s12974-021-02120-3
• 发表时间: 2021-03-12
• 期刊: Journal of neuroinflammation
• 影响因子: 9.3
• 作者: Qi S;Al Mamun A;Ngwa C;Romana S;Ritzel R;Arnold AP;McCullough LD;Liu F
• 通讯作者: Liu F

Cerebrovascular disease in women.

• DOI: 10.1177/1756286420985237
• 发表时间: 2021
• 期刊: Therapeutic advances in neurological disorders
• 影响因子: 5.9
• 作者: Kumar A;McCullough L
• 通讯作者: McCullough L

Sex differences in T cell immune responses, gut permeability and outcome after ischemic stroke in aged mice.

• DOI: 10.1016/j.bbi.2020.02.001
• 发表时间: 2020-07
• 期刊: Brain, behavior, and immunity
• 作者: Ahnstedt H;Patrizz A;Chauhan A;Roy-O'Reilly M;Furr JW;Spychala MS;D'Aigle J;Blixt FW;Zhu L;Bravo Alegria J;McCullough LD
• 通讯作者: McCullough LD

Sex differences in the immune response to acute COVID-19 respiratory tract infection.

• DOI: 10.1186/s13293-021-00410-2
• 发表时间: 2021-12-20
• 期刊: Biology of sex differences
• 影响因子: 7.9
• 作者: Qi S;Ngwa C;Morales Scheihing DA;Al Mamun A;Ahnstedt HW;Finger CE;Colpo GD;Sharmeen R;Kim Y;Choi HA;McCullough LD;Liu F
• 通讯作者: Liu F