Obesity hypertension in African American women: Neuro-metabolic mechanisms

描述(申请人提供)：这项建议的目的是促进Cyndya Shibao博士的科学发展和研究技能，以支持她转变为一名独立的研究人员。范德比尔特大学医学系和临床药理学分部将为施宝博士提供一个理想的环境，在这个环境中研究非裔美国女性肥胖相关高血压的神经代谢机制。通过世宝博士的导师(Italo Biaggioni博士)和共同导师(Naji Abumrad博士)的合作，以及由经验丰富的科学和临床研究人员组成的广泛网络组成的咨询委员会的合作，世宝博士将获得独立学术生涯发展的基础。在她的博士后研究期间，施宝博士获得了必要的经验和研究技能，成功地进行了她申请中提出的研究。这一奖项对于她在新陈代谢领域学习新的科学方法和研究技术，并扩大她以前在心血管和自主神经研究方面的经验将是至关重要的。此外，该奖项将为施宝博士奠定坚实的基础，培养她对与肥胖相关的心血管和代谢紊乱的研究兴趣，并通过参加范德比尔特大学的科学与临床调查硕士课程，为她的培训提供正式的教学课程。与非洲裔美国男性或高加索人相比，非洲裔美国女性肥胖、高血压和胰岛素抵抗的患病率最高。造成这些异常的潜在机制尚不清楚。该提案的总体目标是确定交感神经系统和一氧化氮系统在肥胖相关高血压中的作用。在特定的目标1a中，我们建议检验这一假设，即与高加索人相比，肥胖的非裔美国女性的交感神经对血压的贡献更低。这是基于我们的初步研究，在这些研究中，与高加索人相比，非裔美国女性的交感神经激活增加较少。在这个特定的目标中，我们将使用自主神经节阻滞和曲美沙芬来解决这个问题，并探索这些差异的可能潜在机制，如内脏脂肪质量。尽管我们发现肥胖的非裔美国女性的交感神经激活较少，但与体重指数相同的高加索女性相比，她们的血压仍然有相同的上升。我们的初步结果表明，一氧化氮(NO)可以说是人类血压最重要的代谢调节剂，至少能抑制血压30毫米汞柱。此外，文献中有大量证据表明，非裔美国人的功能没有受损。因此，在特定的目标1b中，我们将检验这一假设，即在非裔美国女性中，受损的血管功能不会导致肥胖相关的高血压。在特定的目标2中，我们将测试这样一个假设，即用磷酸二酯酶-5抑制剂西地那非提高NO功能将逆转非裔美国女性的心血管和代谢变化。在这个项目完成后，我们将获得关于不同种族之间肥胖相关高血压的潜在机制差异的重要知识，我们还将确定旨在逆转这些异常的治疗的潜在目标。

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.