Interplay of Sex Hormones and Chromosomes in Vascular Oxidative Stress and Arterial Stiffening

性激素和染色体在血管氧化应激和动脉硬化中的相互作用

• 批准号: 10672278
• 负责人: Benard Ojwang Ogola
• 金额: $ 24.9万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10672278
• 关键词: Aging; Antioxidants; Aorta; Award; Bioinformatics; Biomechanics; Blood Pressure; Blood Vessels; Cardiovascular Diseases; Cardiovascular Physiology; Cardiovascular system; Cells; Chromosome abnormality; Complement; Data; Development; Disease; Electron Spin Resonance Spectroscopy; Electrons; Ensure; Epigenetic Process; Equipment; Estrogen decline; Estrogens; Fellowship; Female; Flow Cytometry; Fluorescent in Situ Hybridization; Four Core Genotypes; Future; Gene Expression; Genes; Genetic; Genotype; Goals; Gonadal Hormones; Gonadal Steroid Hormones; Health; Hormonal; Hormones; Hypertension; Inflammation; Inherited; Knowledge; Length; Link; Maintenance; Maps; Mediating; Mediator; Menopause; Mentors; Mitochondria; Molecular; Mus; Myography; Outcome; Ovary; Oxidative Stress; Pathway interactions; Phase; Physiologic pulse; Ploidies; Postmenopause; Premenopause; Public Health; Publishing; Pulmonary Hypertension; RNA; Reactive Oxygen Species; Research; Resolution; Role; Science; Sex Chromosomes; Sex Differences; Smooth Muscle Myocytes; Spectrum Analysis; Stroke; Structure; T-Lymphocyte; Techniques; Telemetry; Telomerase; Telomere Shortening; Testing; Testis; Tissues; Training; Transcript; Underrepresented Minority; Untranslated RNA; Woman; X Chromosome; X Inactivation; XX male; Y Chromosome; arterial stiffness; cardiovascular disorder risk; career development; cell type; hormone therapy; improved; in vivo; independency; innovation; male; men; minority scientist; mouse model; novel; preservation; pressure; prevent; programs; protective effect; sex; sexual dimorphism; skills; telomere; transcriptome sequencing; ultrasound

Project Summary Sex steroids and chromosomes both contribute to the sexual dimorphism in CVD. Vascular oxidative stress is one mechanism that is elevated in men compared with women due to the protective effects of estrogen. While the impact of sex hormones is extensively studied, sex chromosomes complementation has been overlooked in the context of CVD. Female sex chromosomes (XX) are associated with worse cardiovascular outcomes during hypertension, stroke, and pulmonary hypertension. Remarkably, studies on the role of sex chromosomes in vascular oxidative stress are still lacking. Therefore, we have proposed to elucidate the role of sex chromosomes in vascular oxidative stress associated with CVD. In the K99 phase, our first aim will establish that in the absence of sex hormones, XX promotes vascular ROS and arterial stiffening. This aim will unequivocally determine the impact of sex chromosomes on arterial stiffness and elucidate the molecular mechanisms. We will use the four core genotype (FCG) mice which includes females with ovaries and testes and males with testes and ovaries. We will also use state-of-the-art equipment such as high resolution ultrasound for pulse wave velocity, biaxial pressure myography for arterial biomechanics, and electron spin spectroscopy for assessing reactive oxygen species. The second aim will elucidate the molecular mechanisms by which estrogen preserves X chromosome inactivation to suppress X-linked gene expression and vascular oxidative stress. We will use fluorescent in situ hybridization to localize X-inactive specific transcript and map the dynamic structure and localization of the sex chromosomes. Our overall goal is to determine whether sex hormones and chromosomes interact in CVD and are associated with vascular oxidative stress. In the future, identifying X-linked genes that contribute to oxidative stress will provide novel targets for sex-specific therapies to treat or prevent CVD. In the R00 phase, the third, fourth and fifth aims will determine whether estrogen mediated Xist RNA localization impacts telomere length, mitochondrial oxidative stress and T-cell mediated vascular damage. The MOSAIC K99/R00 award will enable my training and career development in novel techniques that will allow separation from my mentor and transition to independency. Moreover, this proposal will not only progress scientific research in CVD, but advance the training and fellowship of future minority scientists in biomedical sciences

项目摘要 性类固醇和染色体都导致了脑血管病的性别二型性。 血管氧化应激是男性高于女性的一种机制，由于 雌激素的保护作用。虽然性激素的影响被广泛研究， 在心血管疾病的背景下，性染色体的互补被忽视了。女性性行为 染色体(XX)与高血压期间较差的心血管结局有关， 中风和肺动脉高压。值得注意的是，性染色体在人类基因组中的作用 血管氧化应激仍然缺乏。因此，我们建议澄清 性染色体与心血管疾病相关的血管氧化应激。在K99阶段，我们的第一个 AIM将确定在缺乏性激素的情况下，XX促进血管ROS和动脉ROS 变得僵硬。这一目标将明确确定性染色体对动脉的影响。 并阐明其分子机制。我们将使用四个核心基因(FCG) 小鼠，包括有卵巢和睾丸的雌性和有睾丸和卵巢的雄性。我们会 也使用最先进的设备，如高分辨率超声波来测量脉搏波速度， 动脉生物力学的双轴加压肌造影术和电子自旋光谱分析 评估活性氧物种。第二个目的将阐明分子机制。 雌激素通过哪些途径保持X染色体失活以抑制X连锁基因表达 和血管氧化应激。我们将使用荧光原位杂交来定位X失活基因 性染色体的动态结构和定位。我们的 总体目标是确定性激素和染色体是否在心血管疾病中相互作用，以及 与血管氧化应激有关。在未来，识别与X相关的基因有助于 氧化应激将为针对性别的治疗或预防心血管疾病提供新的靶点。 在R00阶段，第三、第四和第五个AIMS将决定雌激素是否介导Xist RNA定位对端粒长度、线粒体氧化应激和T细胞介导的影响 血管受损。马赛克K99/R00奖将使我的培训和职业发展 在新的技术中，我将与我的导师分开，过渡到独立。 此外，这一建议不仅将促进心血管疾病的科学研究，而且将促进 生物医学科学领域未来少数民族科学家的培训和研究