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

基本信息

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
项目类别：
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

项目摘要

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CVD的性二态性。与应有的女性相比雌激素的保护作用。尽管对性激素的影响进行了广泛的研究，但在CVD的背景下，性染色体互补被忽略了。女性染色体（XX）与高血压期间的心血管结局较差有关，中风和肺动脉高压。值得注意的是，研究性染色体在血管氧化应激仍然缺乏。因此，我们建议阐明与CVD相关的血管氧化应激中的性染色体。在K99阶段，我们的第一个 AIM将确定在没有性激素的情况下，XX促进血管ROS和动脉僵硬。这个目标将明确确定性别染色体对动脉的影响刚度并阐明分子机制。我们将使用四种核心基因型（FCG）包括卵巢和睾丸和雄性睾丸和卵巢的雌性的小鼠。我们将还要使用最先进的设备，例如高分辨率超声以进行脉冲波速度，动脉生物力学和电子自旋光谱法评估活性氧。第二个目标将阐明分子机制通过其中，雌激素保留X染色体灭活以抑制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-Inactive 特定的转录和绘制性别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CVD中相互作用，并且是与血管氧化应激有关。将来，识别有贡献的X连锁基因氧化应激将为性别特异性疗法提供新的靶标，以治疗或预防CVD。在R00阶段，第三，第四和第五目标将决定雌激素是否介导 RNA定位会影响端粒长度，线粒体氧化应激和T细胞介导的血管损伤。 Mosaic K99/R00奖将使我的培训和职业发展能够在新颖的技术中，可以使我的导师和过渡到独立性分开。此外，该提案不仅将在CVD中进行科学研究，而且还可以推进培训生物医学科学的未来少数族裔科学家