Obesity hypertension in African American women: Neuro-metabolic mechanisms

非裔美国女性肥胖高血压：神经代谢机制

• 批准号: 8131080
• 负责人: Cyndya Adriana Shibao
• 金额: $ 15.2万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-18 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8131080
• 关键词: Accounting; Address; Advisory Committees; Affect; African American; Area; Award; Baroreflex; Blood Pressure; Blood Vessels; Body mass index; Cardiovascular Abnormalities; Cardiovascular Diseases; Cardiovascular system; Caucasians; Caucasoid Race; Cause of Death; Clinical; Clinical Pharmacology; Clinical Trials; Collaborations; Complement; Data; Development; Diabetes Mellitus; Fatty Acids; Fatty acid glycerol esters; Fellowship; Fiber; Fostering; Foundations; Functional disorder; Future; Ganglionic Blockers; Gender; Goals; Health; High Prevalence; Human; Hypertension; Insulin; Insulin Resistance; Knowledge; Laboratories; Learning; Leptin; Literature; Master of Science; Measures; Medicine; Mentors; Metabolic; Metabolism; Methods; Nitric Oxide; Obesity; Overweight; Race; Reporting; Research; Research Personnel; Research Technics; Risk; Solid; Sympathetic Nervous System; System; Techniques; Testing; Therapeutic Intervention; Training; Trimethaphan; Universities; Visceral; Woman; base; career; experience; improved; inhibitor/antagonist; interest; men; novel; phosphodiesterase V; public health relevance; racial difference; research and development; research study; restraint; sildenafil; skills

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.

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，以支持她向独立研究者的转变。范德比尔特大学医学系和临床药理学部将为石宝博士提供理想的环境，以研究非裔美国女性肥胖相关高血压的神经代谢机制。通过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广泛网络组成的咨询委员会的合作，Shibao博士将获得发展的基础独立的学术生涯。在博士后研究期间，石宝博士获得了成功开展申请中提出的研究所需的经验和研究技能。该奖项对于她学习新陈代谢领域的新科学方法和研究技术，并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，该奖项将为石宝博士提供坚实的基础，以发展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和临床研究硕士课程来补充她的正式教学课程的培训。 与非裔美国男性或白种人（无论性别）相比，非裔美国女性肥胖、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对肥胖相关高血压的贡献。在具体目标 1a 中，我们建议检验以下假设：与白种人相比，肥胖的非洲裔美国女性的交感神经对血压的贡献较低。这是基于我们的初步研究，其中非裔美国女性的交感神经激活程度低于白人。在这个具体目标中，我们将使用三甲芬阻断自主神经节来解决这个问题，并探索这些差异（例如内脏脂肪量）的可能潜在机制。尽管我们发现肥胖的非洲裔美国女性的交感神经激活程度较低，但与相同体重指数的白人女性相比，她们的血压仍然有相同的升高。我们的初步结果表明，一氧化氮 (NO) 可以说是人类最重要的血压代谢调节剂，可将血压抑制至少 30 毫米汞柱。此外，文献中有大量证据表明非裔美国人的一氧化氮功能受损。因此，在具体目标 1b 中，我们将检验以下假设：在非裔美国女性中，NO 血管功能受损会导致肥胖相关高血压。在具体目标 2 中，我们将检验以下假设：使用磷酸二酯酶 5 抑制剂西地那非增加 NO 功能将逆转非裔美国女性的心血管和代谢变化。该项目完成后，我们将获得有关种族群体之间肥胖相关高血压的潜在机制差异的重要知识，并且我们还将确定旨在逆转这些异常的治疗的潜在目标。 公共卫生相关性：该提案的总体目标是确定交感神经和一氧化氮系统对女性肥胖相关高血压的影响的种族差异。了解这些机制将使我们能够更好地采取有针对性的治疗干预措施，并将影响这种疾病的治疗。