This mid-career development award application is designed to provide critical protected time for the applicant to increase and improve his mentoring activities along with further developing his research program in clinically oriented translational research in vascular biology and endothelial function. During his 12+ years as a faculty member, the applicant has served as research mentor for 17 post-doctoral mentees, including 10 physician- scientists. Nearly 90% percent of the applicant's mentees engaged in patient-oriented research, nearly 50% percent are women, and 82% have remained in academic medicine settings. As part of this program, the applicant will create a more detailed and structured mentorship program for his trainees who are interested in careers in patient-oriented clinical/translational research in vascular biology and physiology. This K24 application is scientifically centered on determining the vascular and inflammatory impact of supplementation of humans with type 2 diabetes (T2DM) with the probiotic Lactobacillus plantarum 299v (Lp299v). This proposal represents a natural outgrowth of the applicant's current work. Despite aggressive traditional risk factor modification and glycemic control efforts with even the most recent glycemic control agents with favorable cardiovascular profiles, atherosclerotic vascular diseases and microvascular disease continue to disproportionately impact individuals with diabetes mellitus (DM). Vascular disease in T2DM begins with the development of vascular endothelial dysfunction. The applicant's group recently reported that once daily supplementation with Lp299v results in improved endothelial function and reduced systemic vascular inflammation in men with stable coronary artery disease. This was the first report of a probiotic supplement having a favorable impact on vascular endothelial function in humans. While this data supports the concept that Lp299v improves vascular endothelial function and reduces systemic inflammation, only three individuals in the pilot study had T2DM. Whether the favorable effects of Lp299v supplementation extend to humans with T2DM remains uncertain. Equipose regarding impact of Lp299v supplementation in human T2DM is further supported by the known significant differences in the composition and metabolism of the gut microbiota of humans with T2DM suggesting the interaction of T2DM gut microbiota with Lp299v may significantly differ compared to those without diabetes. The applicant's preliminary data suggest Lp299v's favorable impact on endothelium-dependent vasodilation and vascular inflammation may be magnified in individuals with T2DM. We will test the hypothesis that Lp299v supplementation improves endothelium-dependent vasodilation and microvascular function, reduces inflammation, and improves insulin sensitivity in humans with T2DM in the setting of a randomized, double-blind, placebo-controlled crossover clinical trial. The proposed studies will both advance our knowledge about a novel method for reducing vascular risk in T2DM through a gut microbiota-targeted intervention and provide an outstanding framework for mentoring the next generation of researchers in vascular-centered patient-oriented research.
Recent human studies report an emerging, novel relationship between the gut microbiome and its metabolites with the development of heart attacks and strokes. This application will determine whether these favorable effects are seen in individuals with type 2 diabetes who have a significantly different gut microbiota and microbiota metabolism than those without type 2 diabetes. Additionally, this application will serve as an excellent platform for mentoring post-doctoral fellows and junior faculty to learn how to conduct impactful patient-oriented human clinical translation research related to vascular biology.