Curcumin Supplementation for Improving Vascular and Cognitive Function

项目摘要 慢性肾脏疾病(CKD)患者死于心血管疾病的风险增加 (CVD)。炎症、氧化应激和血管功能障碍(内皮功能受损和 大弹性动脉僵硬)在慢性肾脏病中非常普遍，并导致高发病率 这一患者群体中的心血管疾病。此外，慢性肾脏病患者的认知功能减退率较高。 我们缺乏有效的治疗方法。因此，针对炎症、氧化应激、 血管功能障碍和认知功能障碍是CKD的生物医学优先事项。 姜黄素是一种天然多酚，具有抗炎和抗氧化的特性。它很安全，而且 随处可见。我们在老年小鼠和健康的中年/老年人类中的初步数据 提示姜黄素通过以下途径改善内皮功能障碍和大动脉僵硬 减少氧化应激和炎症。我们还发现12周的姜黄素补充剂 改善MA/老年人的情景记忆。 此R01应用程序的主要目标是将我们在健康MA/老年人中的发现扩展到患有 CKD，具有广泛基线血管功能障碍和认知功能障碍的不断增长的临床人群 他们目前几乎没有治疗选择。我们认为姜黄素改善血管内皮细胞 患有IIIb和IV期CKD的MA/老年人的功能和大弹性动脉僵硬(估计GFR 15- 45mL/min/1.73m2)。我们还将评估姜黄素改善血管的可能机制。 并确定姜黄素是否改善了这些患者的认知功能。 具体目标1a将确定补充12个月的姜黄素是否会改善臂动脉的血流 中介扩张(BA-FMD)(内皮功能)和主动脉脉搏波速度(APWV)(动脉僵硬) 与安慰剂(随机、安慰剂对照、双盲研究)进行比较。具体目标1b将评估 姜黄素对BA-FMD和aPWV的改善是否与氧化还原有关 应激，并将评估姜黄素对全身和内皮细胞炎症标志物的影响 和氧化应激。重要的是，特殊目标2将评估姜黄素补充剂对 认知功能，CKD的一个重要并发症，使用NIH认知工具箱电池。 这项研究将由临床和翻译中心一个经验丰富的研究团队进行 科罗拉多大学丹佛分校安舒茨医学院研究中心，由Dr。 科罗拉多大学博尔德校区的海豹突击队与斯坦福的田村博士合作 大学。总体而言，该研究有可能影响慢性肾脏病患者的临床实践指南。 通过建立一种新的、安全的、低成本的膳食补充剂来减轻心血管疾病患者的负担 CKD。

Project Summary Patients with chronic kidney disease (CKD) are at increased risk of death from cardiovascular disease (CVD). Inflammation, oxidative stress, and vascular dysfunction (impaired endothelial function and increased large elastic artery stiffness) are highly prevalent in CKD and contribute to the high incidence of CVD in this patient population. In addition, patients with CKD suffer from high rates of cognitive decline for which we lack effective therapies. Thus, therapeutic interventions targeting inflammation, oxidative stress, vascular dysfunction, and cognitive impairment in CKD are a biomedical priority. Curcumin is a natural polyphenol with anti-inflammatory and antioxidant characteristics. It is safe and widely-available. Our preliminary data in old mice and healthy middle-aged (MA)/older adult humans indicate that curcumin administration improves endothelial dysfunction and large artery stiffness by reducing oxidative stress and inflammation. We also found that 12 weeks of curcumin supplementation improves episodic memory in MA/older adults. The primary goal of this R01 application is to extend our findings in healthy MA/older adults to patients with CKD, a growing clinical population with extensive baseline vascular dysfunction and cognitive impairment who presently have few treatment options. We propose that curcumin improves vascular endothelial function and large elastic artery stiffness in MA/older adults with stage IIIb and IV CKD (estimated GFR 15- 45 mL/min/1.73m2). We will also assess the possible mechanisms by which curcumin improves vascular function and determine if curcumin improves cognitive function in these patients. Specific aim 1a will determine if 12 months of curcumin supplementation will improve brachial artery-flow mediated dilation (BA-FMD) (endothelial function) and aortic pulse wave velocity (aPWV) (arterial stiffness) compared to placebo (randomized placebo-controlled double-blind study). Specific aim 1b will evaluate whether the curcumin-induced improvements in BA-FMD and aPWV are mediated by reduced oxidative stress, and will evaluate the effects of curcumin on systemic and endothelial cell markers of inflammation and oxidative stress. Importantly, specific aim 2 will evaluate the effects of curcumin supplementation on cognitive function, an important complication of CKD, using the NIH Cognitive Toolbox Battery. The study will be conducted by a highly experienced team of investigators at the Clinical and Translational Research Center at the University of Colorado-Denver Anschutz Medical Campus with support from Dr. Seals at the University of Colorado Boulder Campus and in collaboration with Dr. Tamura from Stanford University. Overall, the study has the potential to influence clinical practice guidelines in patients with CKD by establishing a novel, safe, and low-cost dietary supplement to reduce the burden of CVD in patients with CKD.