Obesity hypertension in African American women: Neuro-metabolic mechanisms

描述（由申请人提供）：本提案的目的是培养Cyndya Shibao博士的科学发展和研究技能，以支持她过渡到独立研究者。范德比尔特大学医学系和临床药理学学部将为Shibao博士提供理想的环境，研究非裔美国女性肥胖相关高血压的神经代谢机制。通过与Shibao博士的导师（Italo Biaggioni博士）和共同导师（Naji Abumrad博士）以及由经验丰富的科学和临床研究人员组成的顾问委员会的合作，Shibao博士将为独立的学术生涯发展奠定基础。在她的博士后研究期间，Shibao博士获得了必要的经验和研究技能，成功地进行了她申请的研究。这个奖项将对她学习新陈代谢领域的新的科学方法和研究技术，以及扩展她之前在心血管和自主神经研究方面的经验至关重要。此外，该奖项将为Shibao博士提供坚实的基础，以发展她对肥胖相关的心血管和代谢紊乱的研究兴趣，并通过她在范德比尔特大学的科学和临床研究硕士课程的参与，为她的培训提供正式的教学课程。与非裔美国男性或白种人相比，非裔美国女性的肥胖、高血压和胰岛素抵抗患病率最高。造成这些异常的潜在机制尚不清楚。该建议的总体目标是确定交感神经系统和一氧化氮系统对肥胖相关性高血压的贡献。在具体的目的1a中，我们建议验证肥胖的非裔美国妇女的交感神经对血压的影响比白种人低的假设。这是基于我们的初步研究，在研究中，非裔美国女性的交感神经激活的增加比白种人要少。在这个特定的目标中，我们将使用自主神经节阻滞与三甲沙芬来解决这个问题，并探讨这些差异的潜在机制，如内脏脂肪量。尽管我们发现肥胖的非裔美国女性的交感神经活动较少，但与相同体重指数的白人女性相比，她们的血压升高幅度仍然相同。我们的初步研究结果表明，一氧化氮（NO）可以说是人类血压最重要的代谢调节剂，可将其抑制至少30毫米汞柱。此外，文献中有大量证据表明非裔美国人一氧化氮功能受损。因此，在特异性目的1b中，我们将检验非裔美国女性NO血管功能受损导致肥胖相关性高血压的假设。在特定的目标2中，我们将检验用磷酸二酯酶-5抑制剂西地那非增加NO功能将逆转非裔美国妇女心血管和代谢改变的假设。在这个项目完成后，我们将获得关于肥胖相关高血压在种族群体之间潜在机制差异的重要知识，我们也将确定旨在逆转这些异常的治疗的潜在靶点。

DESCRIPTION (provided by applicant): The purpose of this proposal is to foster the scientific development and research skills of Dr. Cyndya Shibao in order to support her transition into an independent investigator. The Department of Medicine and the Division of Clinical Pharmacology at Vanderbilt University will provide Dr. Shibao with the ideal setting in which to investigate the neuro-metabolic mechanisms underlying obesity-associated hypertension in African American women. Through the collaboration of Dr. Shibao's mentor (Dr. Italo Biaggioni) and co-mentor (Dr. Naji Abumrad) and her Advisory Committee composed by an extensive network of experienced scientific and clinical researchers, Dr. Shibao will obtain the foundation for the development of an independent academic career. During her postdoctoral fellowship Dr. Shibao has acquired the necessary experience and research skills to successfully conduct the studies proposed in her application. This award will be critical for her to learn new scientific approaches and research techniques in the area of metabolism, and expand her previous experience on cardiovascular and autonomic research. Furthermore, this award will provide Dr. Shibao with a solid foundation to develop her research interest in the cardiovascular and metabolic derangement associated with obesity, and complement her training with formal didactic courses through her participation in the Master of Science and Clinical Investigation at Vanderbilt University. African American women have the highest prevalence of obesity, hypertension and insulin resistance compared to African American men or Caucasians of either gender. The underlying mechanisms accounting for these abnormalities are unknown. The overall goal of this proposal is to determine the contribution of the sympathetic and nitric oxide systems to obesity-associated hypertension. In specific aim 1a we propose to test the hypothesis that the sympathetic contribution to blood pressure is lower in obese African American women as compared to Caucasians. This is based on our preliminary studies in which African American women have less of an increase in sympathetic activation as compared to Caucasians. In this specific aim we will use autonomic ganglionic blockade with trimethaphan to address this question, and explore possible underlying mechanisms for these differences such as visceral fat mass. Even though we found that obese African American women have less sympathetic activation, they still have the same increase in blood pressure as compared to Caucasian women of the same body mass index. Our preliminary results indicate that nitric oxide (NO) is arguably the most important metabolic modulator of blood pressure in humans, tonically restraining it by at least 30 mm Hg. Moreover, there is substantial evidence in the literature for impaired NO function in African Americans. Therefore, in Specific aim 1b we will test the hypothesis that in African American women impaired NO vascular function contributes to obesity-associated hypertension. In specific aim 2 we will test the hypothesis that increasing NO function with the phosphodiesterase-5 inhibitor, sildenafil, will reverse the cardiovascular and metabolic alterations in African American women. Upon completion of this project, we will have obtained important knowledge about the differences in the underlying mechanisms of obesity-associated hypertension among racial groups and we will also identify potential targets for therapies aimed at reversing these abnormalities. PUBLIC HEALTH RELEVANCE: The overall goal of this proposal is to determine the racial differences in the contribution of the sympathetic and nitric oxide system to obesity associated hypertension in women. Understanding these mechanisms will allow us to better target therapeutic interventions and will impact the treatment of this condition.