Crislip_F32_Childcare Supplement

项目摘要： 超过一半的美国人患有高血压，大多数人的血压（BP）没有得到控制 即使有治疗。需要继续研究了解血压调节以提高治疗效果 和预防血压调节受生物钟的影响，如其每日节律所示。BMAL 1是一个核心 调节生物钟反馈回路的生物钟转录因子。BMAL 1还控制着 数千个对生理功能重要的基因的表达。其他研究表明，全球男性 BMAL 1敲除小鼠（KO）平均动脉压（MAP）降低10 mmHg，并失去昼夜节律 与野生型（WT）相比，BP。因为肾脏是血压的重要调节器，我们产生了远端肾单位- 特异性BMAL 1 KO，其表现出血压差异而不丧失心血管功能的昼夜节律。 我们的初步数据表明，男性KO的血压比WT低约7 mmHg。有趣的是， 这种影响是性别依赖性的，雌性KO具有与WT相当的BP。本研究的目的是确定 性激素影响远端BMAL 1依赖性BP调节的分子机制 男性和女性的肾单位。以前，性激素与血压控制有关。我们假设 男性雄激素对远端肾单位特异性BMAL 1 BP调节的影响与卵巢激素不同 在女性中也是如此。实验将解决我们的假设有两个目标：目标1将测试的假设， 雄性激素信号介导远端肾单位特异性BMAL 1依赖性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BMAL 1依赖性BP变化的假说。 简言之，遥测装置将监测WT和KO伴或不伴性腺切除术和激素的BP 更换.生化分析将确定远端肾单位特异性BMAL 1对这些小鼠BP的作用。 这项提案将研究BMAL 1在血压控制中的作用，而不依赖于昼夜节律，并探讨BMAL 1在血压控制中的作用。 在雄性与雌性中表现出新的差异。该项目还将提供必要的培训， 通过提高科学交流和写作，加强批判性思维能力， 提供指导机会。校园里的科学环境非常支持， 合作，此外，咨询委员会（Karyn Esser博士，Andrew Liu和Arlene Chapman）， 对我的发展至关重要。将昼夜节律生物学原理纳入 这些研究的规划和分析是BP更广泛研究领域的一项关键创新。我们的结果 将提高对外周BMAL 1基因调控的理解，并阐明这些基因调控的多功能性， 昼夜节律基因。此外，我们的研究中纳入女性将产生BMAL 1依赖性的新数据。 血压控制，以前没有探索过，将有助于更好地了解性激素在 血压控制。该应用程序的创新理念旨在扩展我们在BP的知识 并为未来改善人类健康的研究提供基础。

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.