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

这项中期职业发展奖励申请旨在为申请者提供关键的保护时间 增加和改进他的指导活动，同时进一步发展他的临床研究计划 血管生物学和血管内皮细胞功能的定向翻译研究。在他12年多的教职生涯中 成员，申请人曾担任17名博士后导师，其中包括10名医生- 科学家。近90%的申请者指导对象从事以患者为导向的研究，近50% 82%的人是女性，82%的人仍然留在学术医学环境中。作为该计划的一部分， 申请者将为他的实习生创建一个更详细和更有条理的导师计划，他们对 从事以患者为导向的血管生物学和生理学的临床/转化性研究。此K24应用程序 科学上集中在确定补充剂对人体血管和炎症的影响 使用益生菌植物乳杆菌299v(Lp299v)的2型糖尿病(T2 DM)。这项提案代表了 应聘者目前工作的自然结果。尽管激进的传统风险因素修改和 即使是心血管状况良好的最新血糖控制剂也能有效控制血糖， 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人 合并糖尿病(DM)。2型糖尿病血管病变始于血管内皮细胞的发展 功能障碍。申请者小组最近报告说，一旦每天补充Lp299v导致 冠状动脉稳定男性患者的内皮功能改善和全身血管炎症减轻 疾病。这是首次报道益生菌补充剂对血管内皮细胞有有利影响。 在人类身上起作用。虽然这一数据支持Lp299v改善血管内皮功能和 减少全身炎症，在试点研究中只有三个人患有T2 DM。无论是有利的效果 Lp299v补充剂是否适用于患有T2 DM的人类仍不确定。关于影响的均衡 在人类T2 DM中补充Lp299v进一步得到了已知的 T2 DM患者肠道微生物区系的组成和代谢提示T2 DM肠道的相互作用 携带Lp299v的微生物区系可能与未患糖尿病的微生物区系显著不同。申请者的初步申请 数据表明，Lp299v对内皮依赖性血管扩张和血管炎症的有利影响可能 在患有T2 DM的个体中放大。我们将检验补充Lp299v可改善 内皮依赖性血管扩张和微血管功能，减轻炎症，改善胰岛素 随机、双盲、安慰剂对照交叉试验对2型糖尿病患者敏感性的影响 临床试验。拟议中的研究将增进我们对一种减少血管的新方法的了解 通过肠道微生物区系靶向干预降低2型糖尿病的风险，并为指导提供出色的框架 下一代研究人员以血管为中心，以患者为中心的研究。

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.