Impact of L. plantarum 299v supplementation on endothelial function and inflammation in humans with type 2 diabetes

此中期职业发展奖申请旨在为申请人提供关键的保护时间， 增加和改善他的指导活动，沿着进一步发展他的临床研究计划， 在血管生物学和内皮功能方面的定向转化研究。在他12年以上的教师生涯中， 成员，申请人曾担任17名博士后研究生的研究导师，其中包括10名医生- 科学家近90%的申请人的学员从事以患者为导向的研究，近50% 其中80%是女性，82%留在医学院校。作为该计划的一部分， 申请人将创建一个更详细和结构化的导师计划，他的学员谁有兴趣在 在血管生物学和生理学中以患者为导向的临床/转化研究的职业生涯。K24应用 是科学地集中在确定血管和炎症的影响，补充人类 2型糖尿病（T2 DM）患者使用益生菌植物乳杆菌299 v（Lp 299 v）。该提案代表 申请人目前工作的自然结果。尽管积极的传统风险因素修改和 即使是最新的具有良好心血管特性的血糖控制剂的血糖控制努力， 动脉粥样硬化性血管疾病和微血管疾病继续不成比例地影响个体 糖尿病（DM）。2型糖尿病的血管疾病始于血管内皮细胞的发展， 功能障碍申请人的小组最近报道，每天一次补充Lp 299 v导致 改善冠状动脉稳定男性的内皮功能并减少全身血管炎症 疾病这是第一份关于益生菌补充剂对血管内皮细胞有有利影响的报告。 在人类中的功能。虽然该数据支持Lp 299 v改善血管内皮功能的概念， 减少全身性炎症，在初步研究中只有三个人患有T2 DM。是否有利的影响 Lp 299 v补充是否能扩展到T2 DM患者仍不确定。关于以下方面的影响， 人T2 DM中Lp 299 v补充进一步得到了以下已知的显著差异的支持： T2 DM患者肠道微生物群的组成和代谢表明T2 DM肠道 与没有糖尿病的人相比，具有Lp 299 v的微生物群可能显著不同。申请人的初步 数据表明，Lp 299 v对内皮依赖性血管舒张和血管炎症的有利影响可能 在2型糖尿病患者中被放大。我们将检验补充Lp 299 v可以改善 内皮依赖性血管舒张和微血管功能，减少炎症，提高胰岛素 在随机化、双盲、安慰剂对照交叉背景下T2 DM患者中的敏感性 临床试验所提出的研究将推进我们对减少血管生成的新方法的认识。 通过针对肠道微生物的干预，降低T2 DM的风险，并提供出色的指导框架 下一代以血管为中心、以患者为导向的研究人员。

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.