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

项目摘要 性激素和染色体都有助于CVD的两性异形。 血管氧化应激是一种机制，与女性相比，男性的氧化应激水平升高， 雌激素的保护作用虽然性激素的影响被广泛研究， 性染色体互补在CVD中被忽视。女性性 染色体（XX）与高血压期间更差的心血管结局相关， 中风和肺动脉高压。值得注意的是，关于性染色体在 血管氧化应激仍然缺乏。因此，我们建议阐明 性染色体与CVD相关的血管氧化应激在K99阶段，我们的第一个 我们的目标是确定在缺乏性激素的情况下，XX促进血管ROS和动脉 硬化这一目标将明确地确定性染色体对动脉粥样硬化的影响。 刚度和阐明分子机制。我们将使用四个核心基因型（FCG） 小鼠，包括具有卵巢和睾丸的雌性和具有睾丸和卵巢的雄性。我们将 也可以使用最先进的设备，如用于脉搏波速度的高分辨率超声波， 双轴压力肌造影用于动脉生物力学，电子自旋光谱用于 评估活性氧物质。第二个目标将阐明分子机制 雌激素通过保持X染色体失活来抑制X连锁基因的表达 和血管氧化应激。我们将使用荧光原位杂交定位X-非活性 特异性转录本，绘制性染色体的动态结构和定位。我们 总体目标是确定性激素和染色体是否在CVD中相互作用， 与血管氧化应激有关。在未来，确定X连锁基因， 将为性别特异性治疗提供新的靶点，以治疗或预防CVD。 在R 00阶段，第三、第四和第五个目标将确定雌激素是否介导Xist RNA定位影响端粒长度、线粒体氧化应激和T细胞介导的 血管损伤MOSAIC K99/R 00奖将使我的培训和职业发展 新的技术，这将允许从我的导师分离和过渡到独立。 此外，这一建议不仅将推动CVD的科学研究， 未来少数民族生物医学科学家的培训和研究金

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