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

项目摘要 嗅觉受体（ORs）是基因组中最大的基因家族，ORs在嗅觉系统中起着关键作用。 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 OR，Olfr 558，定位于血管平滑肌细胞并在血压中起作用 调控在人类和动物模型中，血压正常的 绝经前女性的血压比血压正常的男性低大约 ~ 10 mmHg。相比之下，绝经后女性和男性的血压相似， 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Olfr 558敲除（KO）小鼠中不存在，并且野生型（WT）而非KO雌性增加 血压随着年龄的增长在这个提议中，我们将探讨Olfr 558在介导 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小鼠之间的差异，所述小鼠是年轻的（4-7个月，雄性和雌性）、年老的（18-22 3个月，男性和女性），或年轻（4-7个月）的女性，其中更年期已经 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 这些相同的小鼠来测定WT中的肾素（Aim 2a）和血管反应性（Aim 2b）如何改变 与KO相比。这些研究将揭示一个保守的OR在 老化的心血管生理学，并在这样做将揭示新的见解性 差异、血压调节、衰老和更年期。

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.