Non-coding RNA regulation of sex differences in stroke

非编码RNA对中风性别差异的调节

• 批准号: 10605234
• 负责人: Creed Michael Stary
• 金额: $ 36.12万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10605234
• 关键词: 3' Untranslated Regions; Acute; Advanced Development; Affect; Animals; Apoptosis Inhibitor; Astrocytes; Biological; Biological Phenomena; Brain; Brain Injuries; Cause of Death; Cell Culture Techniques; Cell Death; Cell Survival; Cell physiology; Cells; Cessation of life; Clinical; Clinical Treatment; Clinical Trials; Data; Development; Disease; Elderly; Evolution; Experimental Models; Failure; Female; Fluorescent in Situ Hybridization; Functional disorder; Gene Expression Regulation; Gene Targeting; Generations; Genes; Glucose; Immunohistochemistry; In Vitro; Incidence; Injury; Intravenous; Investigation; Ischemia; Knowledge; Life; Link; Mediating; MicroRNAs; Middle Cerebral Artery Occlusion; Mitochondria; Molecular; Mus; Nerve Growth Factors; Neurodegenerative Disorders; Neurons; Outcome; Oxidative Phosphorylation; Pathogenesis; Pathway interactions; Pharmaceutical Preparations; Pharmacological Treatment; Play; Prevalence; Process; Proteins; RNA immunoprecipitation sequencing; RNA methylation; Reactive Oxygen Species; Regulation; Regulator Genes; Reperfusion Therapy; Resolution; Rodent; Role; SIRT1 gene; Sex Differences; Site; Small Interfering RNA; Source; Spirometry; Stroke; Testing; Therapeutic; Untranslated RNA; Woman; Work; age related; aged; brain cell; cell type; cohort; comparative; design; disability; fluorescence imaging; in vivo; in vivo evaluation; ischemic injury; long term recovery; male; men; mitochondrial dysfunction; novel; post stroke; pre-clinical; pre-clinical research; preclinical study; reelin protein; response; response to injury; sex; sexual dimorphism; stroke outcome; stroke therapy; translation factor; translational barrier; trend; young adult

Stroke remains the second leading cause of death worldwide and the primary cause of long-term disability in the US. Although pre-clinical studies have identified hundreds of potential drug agents, the only pharmacological treatment available remains early reperfusion with thrombolytics. A major factor for translational failure may be the overwhelming use of young male rodents in pre-clinical research, and lack of sex-specific design and analysis in clinical trials. Stroke is a sexually dimorphic disease with sex differences in incidence, prevalence, and outcome. Mitochondria mediate post-ischemia cell death in both males and females, but in different manners. Non-coding RNAs, including microRNAs (miRs), are upstream regulators of genes that regulate cell survival and mitochondrial function. In young adult male animals, miRs have been established as central regulators in the cellular response to stroke, however their role in females or aged animal cohorts represents a critical knowledge gap. Our prior studies (2, 4) and preliminary evidence suggest age-related differences between females and males in expression of select miRs and their targets following stroke. The overarching hypothesis of these Aims is that expression and function of miR-181a and miR-200c is a critical determinant of sexual dimorphism in stroke outcomes. To test this, we will first compare aged (20 month old) female and male mice using the middle cerebral artery occlusion (MCAO) model of experimental stroke, then compare primary female and male neuronal and astrocyte cultures utilizing in vitro ischemia. Preliminary evidence in aged animals reveals only a modest post- MCAO miR-181a response that is limited to females, while comparatively, a pronounced miR-200c response occurs in both sexes. Moreover, our preliminary evidence implies sex-differences in miR-181a and miR-200c gene targeting. In Aim 1, we will first compare protection with post-MCAO IV treatment of anti-miR-181a or anti- miR-200c in aged males and females. Then, we will assess the long-term cell-specific and sex-specific response in miR-181a and miR-200c to MCAO. Next, we will compare sustained post-MCAO miR-200c inhibition on long- term neuro-recovery between aged males and females, with the basis that preliminary evidence implies female- specific targeting of the neurotrophic protein reelin by miR-200c. In Aim 2, we will: 1) focus on the roles of miR- 181a and miR-200c in differences in regional (core versus penumbra) post-stroke disruption in mitochondrial function between aged males and females; and, 2) determine the roles of miR-181a and miR-200c in cell-type, and sex-specific alterations in oxidative phosphorylation and disruptions in cytosolic and mitochondrial Ca2+- handling following in vitro ischemia. In Aim 3 we will first define cell-type and sex-dependent differential gene targeting by miR-181a (Grp78 and XIAP) and miR-200c (XIAP, sirtuin-1, reelin). Finally we will determine whether observed differential gene targeting could be attributed to differences in RNA methylation, and whether this changes in response to injury. Delineating the molecular mechanisms that determine sexual dimorphism in stroke is necessary to overcome translational barriers and advance the development of novel stroke treatments.

中风仍然是全球第二大死亡原因，也是美国长期残疾的主要原因

项目成果

Extracellular vesicle-derived miRNA as a novel regulatory system for bi-directional communication in gut-brain-microbiota axis.

细胞外囊泡衍生的miRNA作为肠道 - 毛 - 微生物轴双向通信的新型调节系统。

• DOI: 10.1186/s12967-021-02861-y
• 发表时间: 2021-05-11
• 期刊: Journal of translational medicine
• 影响因子: 7.4
• 作者: Zhao L;Ye Y;Gu L;Jian Z;Stary CM;Xiong X
• 通讯作者: Xiong X

Expression of miR-200c corresponds with increased reactive oxygen species and hypoxia markers after transient focal ischemia in mice.

• DOI: 10.1016/j.neuint.2021.105146
• 发表时间: 2021-10
• 期刊: Neurochemistry international
• 影响因子: 4.2
• 作者: Arvola O;Griffiths B;Rao A;Xu L;Pastroudis IA;Stary CM
• 通讯作者: Stary CM

Inhibition of microRNA-200c preserves astrocyte sirtuin-1 and mitofusin-2, and protects against hippocampal neurodegeneration following global cerebral ischemia in mice.

• DOI: 10.3389/fnmol.2022.1014751
• 发表时间: 2022
• 期刊: FRONTIERS IN MOLECULAR NEUROSCIENCE
• 影响因子: 4.8
• 作者: Griffiths, Brian;Xu, Lijun;Sun, Xiaoyun;Greer, Majesty;Murray, Isabella;Stary, Creed
• 通讯作者: Stary, Creed

MiR-182 Inhibition Protects Against Experimental Stroke in vivo and Mitigates Astrocyte Injury and Inflammation in vitro via Modulation of Cortactin Activity.

• DOI: 10.1007/s11064-022-03718-6
• 发表时间: 2022-12
• 期刊: NEUROCHEMICAL RESEARCH
• 影响因子: 4.4
• 作者: Alhadidi, Qasim M.;Xu, Lijun;Sun, Xiaoyun;Althobaiti, Yusuf S.;Almalki, Atiah;Alsaab, Hashem O.;Stary, Creed M.
• 通讯作者: Stary, Creed M.