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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要嗅觉受体 (OR) 包含基因组中最大的基因家族，OR 发挥着关键作用在鼻子以外的多种组织中发挥作用。我们发现了一个进化上保守的 OR，Olfr558，定位于血管平滑肌细胞并在血压中发挥作用规定。在人类和动物模型中，众所周知，正常血压绝经前女性的血压比血压正常男性低约〜10毫米汞柱。相反，绝经后女性和男性的血压相似，因为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 Olfr558 敲除 (KO) 小鼠中不存在，并且野生型 (WT) 而非 KO 雌性小鼠中不存在增加血压随年龄增长。在本提案中，我们将探讨 Olfr558 在调解中的作用衰老过程中血压的变化。在目标 1 中，我们将通过遥测技术比较血压在年轻（4-7 个月，雄性和雌性）、年龄（18-22 岁）的 WT 和 KO 小鼠之间进行比较月，男性和女性），或已绝经的年轻女性（4-7个月）通过 VCD（4-乙烯基环己烯二环氧化合物）化学诱导。在目标 2 中，我们将使用来自使用这些相同的小鼠来检测 WT 中肾素 (Aim 2a) 和血管反应性 (Aim 2b) 的变化情况在这些不同的组中对阵 KO。这些研究将揭示保守的 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。