PROJECT SUMMARY/ABSTRACT
The purpose of this K99/R00 application is to provide support for Dr. Vienna Brunt, a promising postdoctoral
fellow in the laboratory of Dr. Douglas Seals, to conduct additional research and training that will allow her to
successfully transition into an independent investigator in the field of translational cardiovascular aging and the
prevention of cardiovascular diseases (CVD). As part of her proposed K99 training plan, she will learn new
technical skills, enhance her intellectual and professional skills, gain valuable mentorship and participate in
various career development activities, including those that will help establish her as a leader in the field of gut
microbiome-related cardiovascular research. Her proposed research project seeks to investigate the effects of
oral supplementation with the short-chain fatty acid acetate on improving age-related arterial dysfunction
(i.e., the primary risk factor for CVD), first in mice (K99 phase) and later in humans (R00 phase). Short-chain
fatty acids are byproducts of gut microbiome-dependent fermentation of dietary soluble fiber and are thought to
mediate many of the health benefits of high-fiber diets. Guided by strong preliminary data, Dr. Brunt will first
(Aim 1) confirm efficacy of acetate supplementation for improving arterial function in old mice. With guidance
and training in technical skills from leading experts in mechanistic cardiovascular research, she will then (Aim
2) conduct innovative siRNA experiments in both mouse isolated arteries and cultured endothelial cells to
determine the mechanisms of acetate-mediated improvements in arterial function, specifically the roles of free
fatty acid receptor (FFAR)3 and downregulation of the cardiopathological transcription factor early growth
response-1 (Egr-1). After transitioning to a faculty position, Dr. Brunt will next (Aim 3; R00 phase) translate her
findings to humans by conducting a randomized, placebo-controlled, double-blind, parallel-design clinical trial
in late middle-aged to older (³50 years) adults investigating the effects of 12 weeks of oral supplementation
with acetate on arterial function. She will also use cutting-edge in vivo and ex vivo approaches to elucidate the
underlying mechanisms. Overall, the proposed research has the potential to address 2 important strategic
research priorities of NHLBI: 1) investigate new pathobiological mechanisms important to the onset of CVD,
and 2) identify a novel therapeutic strategy to prevent and treat age-associated arterial dysfunction, thereby
reducing risk of CVD. The proposed research will provide numerous ideas and opportunities for future fundable
research, culminating in submission of a novel R01 during years 4-5 of this award. The primary mentor, Dr.
Seals, is an internationally-recognized and NIH funded scientist with a strong history of successful mentoring in
translational cardiovascular research. With his guidance and the guidance of co-mentor Dr. Leslie Leinwand,
advisory team members Drs. Mike Widlansky, Dr. Rob Knight, and Michel Chonchol, and biostatistician Dr.
Zhiying You, Dr. Brunt will be able to successfully complete the proposed research and training plan and
transition to an independent, extramurally-funded tenure-track position at a top-tier (R1) research institution.