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 1 a 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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Mentored Patient-Oriented Research Career Development Award (K23)
Project #
5K23HL103976-03
Application #
8269890
Study Section
Special Emphasis Panel (ZHL1-CSR-R (M1))
Program Officer
Scott, Jane
Project Start
2010-08-18
Project End
2015-05-31
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
3
Fiscal Year
2012
Total Cost
$152,010
Indirect Cost
$11,260
Name
Vanderbilt University Medical Center
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Arnold, Amy C; Okamoto, Luis E; Gamboa, Alfredo et al. (2016) Mineralocorticoid Receptor Activation Contributes to the Supine Hypertension of Autonomic Failure. Hypertension 67:424-9
Shah, Sapna S; Ramirez, Claudia E; Powers, Alvin C et al. (2016) Hyperglycemic clamp-derived disposition index is negatively associated with metabolic syndrome severity in obese subjects. Metabolism 65:835-42
Shibao, Cyndya A; Celedonio, Jorge E; Ramirez, Claudia E et al. (2016) A Common CD36 Variant Influences Endothelial Function and Response to Treatment with Phosphodiesterase 5 Inhibition. J Clin Endocrinol Metab 101:2751-8
Marinos, Alejandro; Celedonio, Jorge E; Ramirez, Claudia E et al. (2015) Time-Course Analysis of Flow Mediated Dilation for the Evaluation of Endothelial Function After a High-Fat Meal in African Americans. J Am Heart Assoc 4:
Celedonio, Jorge E; Arnold, Amy C; Dupont, William D et al. (2015) Residual sympathetic tone is associated with reduced insulin sensitivity in patients with autonomic failure. Clin Auton Res 25:309-15
Ramirez, Claudia E; Nian, Hui; Yu, Chang et al. (2015) Treatment with Sildenafil Improves Insulin Sensitivity in Prediabetes: A Randomized, Controlled Trial. J Clin Endocrinol Metab 100:4533-40
Bi, X; Seabolt, L; Shibao, C et al. (2015) DXA-measured visceral adipose tissue predicts impaired glucose tolerance and metabolic syndrome in obese Caucasian and African-American women. Eur J Clin Nutr 69:329-36
Johnson, Davalynn A; Joosten, Yvonne A; Wilkins, Consuelo H et al. (2015) Case Study: Community Engagement and Clinical Trial Success: Outreach to African American Women. Clin Transl Sci 8:388-90
Arnold, Amy C; Ramirez, Claudia E; Choi, Leena et al. (2014) Combination ergotamine and caffeine improves seated blood pressure and presyncopal symptoms in autonomic failure. Front Physiol 5:270
Ferguson, Marcus C; Garland, Emily M; Hedges, Lora et al. (2014) SHC2 gene copy number in multiple system atrophy (MSA). Clin Auton Res 24:25-30

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