Olfactory Receptor 558 (Olfr558) and Blood Pressure Regulation in Aging

嗅觉受体 558 (Olfr558) 和衰老过程中的血压调节

• 批准号: 10646623
• 负责人: Jennifer L Pluznick
• 金额: $ 24.56万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-15 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10646623
• 关键词: 4-vinylcyclohexene diepoxide; Acetates; Address; Age; Aging; Animal Model; Binding; Biological Assay; Blood Pressure; Blood Vessels; Butyrates; Carbon; Cardiovascular Physiology; Cardiovascular system; Cell physiology; Cells; Chemicals; Chemoreceptors; Data; Female; G-Protein-Coupled Receptors; Gene Family; Genome; Human; Hypertension; In Vitro; Individual; Juxtaglomerular Apparatus; Kidney; Knock-out; Knockout Mice; Ligands; Measures; Mediating; Mediator; Menopause; Modeling; Mus; Nose; Organ; Orthologous Gene; Pathway interactions; Peripheral; Phenotype; Physiological; Play; Postmenopause; Premenopause; Propionates; Regulatory Pathway; Renin; Reporting; Role; Sampling; Sex Differences; Signal Transduction; Smooth Muscle Myocytes; Telemetry; Testing; Time; Tissues; Translations; Vascular Smooth Muscle; Volatile Fatty Acids; Wild Type Mouse; Woman; Work; aged; arteriole; blood pressure elevation; blood pressure reduction; blood pressure regulation; cell type; falls; gut microbes; gut microbiota; human model; insight; knockout animal; male; men; middle age; mouse model; normotensive; novel; olfactory receptor; placental mammal; public health relevance; reproductive function

Project Summary Olfactory Receptors (ORs) comprise the largest gene family in the genome, and ORs serve key functions in a variety of tissues beyond the nose. We have identified an evolutionarily conserved OR, Olfr558, which localizes to vascular smooth muscle cells and plays a role in blood pressure regulation. It is well-established, in both humans and in animal models, that normotensive premenopausal females have lower blood pressure than normotensive males by approximately ~10mmHg. In contrast, blood pressure is similar in postmenopausal females and males, due to an increase in female blood pressure with aging. We find that sex differences in blood pressure are absent in Olfr558 knockout (KO) mice, and, that wild-type (WT) but not KO females increase blood pressure with aging. In this proposal, we will explore the role of Olfr558 in mediating changes in blood pressure in aging. In Aim 1, we will compare blood pressure by telemetry between WT and KO mice which are young (4-7 months, male and female), aged (18-22 months, male and female), or young (4-7 months) females in whom menopause has been chemically induced via VCD (4-vinylcyclohexene diepoxide). In Aim 2, we will use tissues from these same mice to assay how renin (Aim 2a) and vascular reactivity (Aim 2b) are altered in WT vs KO in these various groups. These studies will uncover the role of a well-conserved OR in the cardiovascular physiology of aging, and in so doing will reveal novel insights into sex differences, blood pressure regulation, aging, and menopause.

项目摘要 嗅觉受体是基因组中最大的基因家族，嗅觉受体起着关键作用 在鼻子以外的各种组织中发挥作用。我们发现了一种进化上保守的 或者，Olfr558，它定位于血管平滑肌细胞，在血压中起作用 监管。在人类和动物模型中，血压正常是公认的 绝经前女性的血压比血压正常的男性低大约 ~10毫米汞柱。相比之下，绝经后女性和男性的血压相似，原因是 女性血压随着年龄的增长而升高。我们发现血压的性别差异 在Olfr558基因敲除(KO)小鼠中不存在，野生型(WT)而不是KO雌性小鼠增加 血压随着年龄的增长而变化。在这项提案中，我们将探讨Olfr558在调解中的作用 血压在衰老过程中的变化。在目标1中，我们将通过遥测来比较血压 WT和KO小鼠之间是年轻的(4-7月龄，雌雄)，年龄(18-22岁) 男性和女性)或年轻女性(4-7个月) 通过VCD(4-乙烯基环己烯二环氧化物)化学诱导。在目标2中，我们将使用来自 以测试WT中肾素(Aim 2a)和血管反应性(Aim 2b)是如何改变的 VS KO在这些不同的小组中。这些研究将揭示保存完好的OR在 衰老的心血管生理学，这样做将揭示对性的新见解 差异、血压调节、衰老和更年期。