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.
This application examines the role of circadian clock proteins in the kidney and their contribution to blood pressure regulation. Preliminary data have demonstrated a sex-specific affect, therefore, studies proposed in this application will include both male and female mice to determine the role of sex hormones in this relationship. Not only will the novelty of our hypotheses provide answers to gaps in the literature, but the process will also offer valuable training for the advancement of my career.
