The Role of Sex Hormones in Distal Nephron-Specific BMAL1 Blood Pressure Regulation in Male and Female Mice

项目总结： 超过一半的美国人患有高血压，大多数人的血压没有得到控制 即使接受了治疗。需要继续研究了解BP的调节以提高治疗效果 和预防。血压的调节受生物钟的影响，从昼夜节律可以看出。BMal1是一个核心 调节生物钟反馈环路的昼夜节律转录因子。BMal1还控制 对生理功能很重要的数千个基因的表达。其他人则表明，全球男性 BMal1基因敲除小鼠(KO)平均动脉压(MAP)降低10毫米汞柱，并失去昼夜节律 BP与野生型(WT)的比较。因为肾脏是血压的关键调节器，我们产生了远端肾单位- 特定的BMAL1 KO表现出不同的血压而不会失去心血管功能的昼夜节律。 我们的初步数据显示，男性KO的血压比WT低约7毫米汞柱。有趣的是， 这种影响是性别依赖的，女性KO的血压与WT相当。这项研究的目标是确定 性激素影响远端BMAL1依赖的BP调节的分子机制 男性和女性的肾单位。性激素此前曾被认为与血压控制有关。我们假设 男性雄激素对远端肾单位特异性BMAL1BP调节的影响不同于卵巢激素 在女性身上也是如此。实验将解决我们的假设有两个目的：目标1将测试假设 男性性激素信号介导远端肾单位特异性BMAL1依赖的BP调节。目标2将测试 女性卵巢激素阻止远端肾单位特异性BMAL1依赖性血压改变的假说。 简而言之，遥测设备将监测有或没有性腺切除和激素的WT和KO患者的血压 替补。生化分析将确定远端肾单位特异性BMAL1对这些小鼠血压的作用。 这项建议将研究BMAL1在独立于昼夜节律的血压控制中的作用，并探索 在男性和女性身上表现出了新的差异。该项目还将提供必要的培训，以帮助 通过改善科学交流和写作，加强批判性思维能力，促进我的事业发展，以及 提供辅导机会。校园里的科学环境非常支持和支持 此外，协作性的咨询委员会(Karyn Esser博士、Andrew Liu博士和Arlene Chapman博士) Gumz和我的合作将对我的发展起到至关重要的作用。将昼夜节律生物学原理纳入 这些研究的规划和分析是BP研究更广泛领域的一项关键创新。我们的结果 将提高对外周BMAL1基因调控的理解，并阐明这些基因的多功能性 昼夜节律基因是。此外，将女性纳入我们的研究将产生关于BMAL1依赖的新数据 以前从未探索过的BP控制，将有助于更好地理解性激素在 BP控制中心。处于这一应用前沿的创新想法旨在扩大我们对BP的了解 并为今后改善人类健康的研究提供了基础。

Project Summary: Over half of Americans have hypertension and the majority do not have their blood pressure (BP) under control even with treatment. Continued research in understanding BP regulation is needed to improve treatment efficacy and prevention. BP regulation is influenced by the circadian clock as seen by its daily rhythm. BMAL1 is a core circadian transcription factor which regulates the circadian clock feedback loop. BMAL1 also controls the expression of thousands of genes important for physiological functions. Others have shown that male global BMAL1 knockout mice (KO) have 10 mmHg lower mean arterial pressure (MAP) and lose their circadian rhythm in BP compared to wildtype (WT). Because the kidney is a critical regulator of BP, we generated distal nephron- specific BMAL1 KO that exhibit a difference in BP without loss of circadian rhythms in cardiovascular function. Our preliminary data demonstrate that male KO have approximately 7 mmHg lower BP than WT. Interestingly, this affect is sex-dependent and female KO have comparable BP to WT. The goal of this study is to determine the molecular mechanisms by which sex hormones influence BMAL1-dependent BP regulation in the distal nephron in males and females. Sex hormones have been linked to BP control previously. We hypothesize that androgens in males influence distal nephron-specific BMAL1 BP regulation differently than ovarian hormones do so in females. Experiments will address our hypothesis with two aims: Aim 1 will test the hypothesis that male sex hormone signals mediate distal nephron-specific BMAL1-dependent BP regulation. Aim 2 will test the hypothesis that ovarian hormones in females prevent distal nephron-specific BMAL1-dependent changes in BP. Briefly, telemeter devices will monitor BP in WT and KO with and without gonadectomy and hormone replacement. Biochemical assays will determine the role of distal nephron-specific BMAL1 on BP in these mice. This proposal will examine the role of BMAL1 in BP control independent of circadian rhythms and explore the novel difference demonstrated in males vs. females. This project will also provide essential training to help in advancing my career by improving scientific communication and writing, strengthening critical thinking skills, and providing mentorship opportunities. The scientific environment on campus is extremely supportive and collaborative, additionally, the advisory committee (Drs. Karyn Esser, Andrew Liu, and Arlene Chapman) that Dr. Gumz and I have assembled will be critical in my development. The inclusion of circadian biology principles in the planning and analysis of these studies is a key innovation in the broader field of BP research. Our results will improve the understanding of peripheral BMAL1 gene regulation and shed light on how versatile these circadian genes are. Additionally, inclusion of females in our study will yield novel data on BMAL1-dependent BP control that has not been explored before and will aide in better understanding the role of sex hormones in BP control. The innovative ideas that are at the forefront of this application aim to expand our knowledge in BP regulation and provide a basis for future studies that will improve human health.