Crislip_F32_Childcare Supplement

Crislip_F32_育儿补充剂

• 批准号: 10397263
• 负责人: Gene Ryan Crislip
• 金额: $ 0.25万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-15 至 2022-03-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10397263
• 关键词: ARNTL gene; Address; Adult; Advisory Committees; Affect; American; Androgens; Animals; Area; Biochemical; Biological Assay; Biology; Blood Pressure; Blood Pressure Monitors; Cadherins; Cardiovascular Physiology; Circadian Rhythms; Clock protein; Communication; Critical Thinking; Data; Development; Devices; Dissection; Distal; Environment; Exhibits; Feedback; Female; Future; Gene Expression Regulation; Genes; Goals; Gonadal Steroid Hormones; Health; Heterogeneity; Hormones; Human; Hypertension; Institution; Kidney; Knockout Mice; Knowledge; Lead; Light; Link; Literature; LoxP-flanked allele; Mediating; Mentorship; Metabolic; Methods; Modeling; Molecular; Monitor; Mus; Nephrons; Operative Surgical Procedures; Orchiectomy; Organ; Ovarian hormone; Ovariectomy; Pathway interactions; Peripheral; Phenotype; Physiological; Plasma; Play; Prevention; Process; Rattus; Regulation; Research; Research Personnel; Resistance; Role; Single Nucleotide Polymorphism; Stroke; Testing; Training; Treatment Efficacy; Tubular formation; Writing; blood pressure reduction; blood pressure regulation; career; circadian; circadian pacemaker; design; experimental study; female sex hormone; heart disease risk; hormonal signals; improved; innovation; insight; male; male sex hormones; mouse model; novel; pressure; prevent; sex; skills; transcription factor

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.

项目概要： 超过一半的美国人患有高血压，并且大多数人的血压 (BP) 没有得到控制 即使接受治疗。需要继续研究了解血压调节以提高治疗效果 和预防。从每日节律来看，血压调节受到生物钟的影响。 BMAL1是核心 调节生物钟反馈环路的昼夜节律转录因子。 BMAL1 还控制 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 BMAL1 基因敲除小鼠 (KO) 的平均动脉压 (MAP) 降低 10 mmHg，并失去昼夜节律 与野生型 (WT) 相比，在 BP 中。由于肾脏是血压的关键调节者，我们生成了远端肾单位 特定的 BMAL1 KO 表现出血压差异，但心血管功能的昼夜节律不丧失。 我们的初步数据表明，雄性 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，女性 KO 的血压与 WT 相当。本研究的目标是确定 性激素影响远端BMAL1依赖性血压调节的分子机制 男性和女性的肾单位。此前，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 BMAL1 BP 调节的影响与卵巢激素不同 在女性中这样做。实验将通过两个目标来解决我们的假设： 目标 1 将检验以下假设： 男性性激素信号介导远端肾单位特异性 BMAL1 依赖性血压调节。目标 2 将测试 假设女性卵巢激素可防止远端肾单位特异性 BMAL1 依赖性血压变化。 简而言之，遥测设备将监测 WT 和 KO 患者的血压，无论是否进行性腺切除术和激素 替代品。生化检测将确定远端肾单位特异性 BMAL1 对这些小鼠血压的作用。 该提案将研究 BMAL1 在独立于昼夜节律的血压控制中的作用，并探索 男性与女性之间表现出新的差异。该项目还将提供必要的培训，以帮助 通过改善科学沟通和写作、加强批判性思维能力来推进我的职业生涯，以及 提供指导机会。校园里的科学环境非常支持和 此外，咨询委员会（Karyn Esser 博士、Andrew Liu 博士和 Arlene Chapman）也表示合作。 我和古姆兹的集结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更广泛的 BP 研究领域的一项关键创新。我们的成果 将提高对外周 BMAL1 基因调控的理解，并揭示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中将产生有关 BMAL1 依赖性的新数据 以前从未探索过的血压控制将有助于更好地了解性激素在 血压控制。该应用最前沿的创新理念旨在扩展我们在 BP 方面的知识 监管并为未来改善人类健康的研究奠定基础。

项目成果

Adrenal-Specific KO of the Circadian Clock Protein BMAL1 Alters Blood Pressure Rhythm and Timing of Eating Behavior.

肾上腺特异性敲除生物钟蛋白 BMAL1 会改变血压节律和饮食行为时间。

• 发表时间: 2023
• 作者: Costello, Hannah M;Crislip, G Ryan;Cheng, Kit;Lynch, I Jeanette;Juffre, Alexandria;Bratanatawira, Phillip;Mckee, Annalisse;Thelwell, Ryanne S;Mendez, Victor M;Wingo, Charles S;Douma, Lauren G;Gumz, Michelle L
• 通讯作者: Gumz, Michelle L