Immune mechanisms of Vitamin D in a randomized controlled trial to reduce chronic pain after burn.

项目总结/摘要 在美国，每年约有500，000人在烧伤后寻求护理，约有40，000人遭受严重热烧伤（MThBI），需要住院治疗。大约四分之三的住院MThBI幸存者需要皮肤移植，这是一种将皮肤或其他材料应用于烧伤部位（移植部位）的外科手术。接受皮肤移植的人中有一半以上会出现严重的持续性移植部位疼痛。迫切需要新的非阿片类药物干预措施来改善接受皮肤移植的MThBI幸存者的疼痛结局。 重要的是，科学界越来越认识到，投资数百万美元在传统的随机对照试验上，只提供一个“竖起大拇指或向下”的结果，是一个糟糕的科学投资。当（1）干预措施已被证明有效地参与靶向生物学机制时，RCT提供了更大的价值，（2）试验评估了假设的机制是否介导了任何观察到的治疗效果。在K12获奖期间，我获得了进行和分析传统随机对照试验（RCT）的宝贵技能和培训，以及在MThBI人群中进行研究的经验。此外，从我的试点干预试验中获得的数据测试了维生素D（vit D）改善MThBI疼痛结果的能力，支持这种天然产品干预的安全性，可行性和令人兴奋的潜力，以减少或预防MThBI后的慢性疼痛。维生素D是一种有前途的，低成本的，广泛可用的干预措施，具有有效的抗炎和神经保护特性。维生素D已被证明对免疫细胞群具有强大的作用，并已被证明可以改善一系列神经/炎症性疾病的疼痛和相关结果。 这个为期3年的NCCIH K23将建立在我的K12培训的基础上，并将为我提供必要的技能和经验，以在MThBI幸存者中进行“最先进”的维生素D机制试验。具体而言，在K23期间，我将学习将最新的质谱细胞术方法应用于从RCT参与者获得的系列血液样本，以评估循环维生素D水平的增加导致（1）抗炎单核细胞表型和调节性T细胞增加的程度，以及（2）促炎性Toll样受体4信号传导和效应T细胞（例如，Th1和Th17细胞）。此外，我将学习使用先进的统计方法（弹性网络算法和多个并行中介模型）来评估这些免疫细胞的变化是否介导治疗效果，并根据关键心理社会因素的任何基线差异进行调整。 慢性疼痛发展的免疫机制的研究是一个丰富的，令人兴奋的，新兴的科学领域。拟议的K23活动不仅是理想的评估维生素D目标参与和机制的假设在MThBI幸存者，但也将为我提供一个良好的技能基础的职业生涯作为一个NIH资助的慢性疼痛研究人员和临床试验。总之，在我3年的NCCIH K23期间获得的技能和培训将使我从一个“竖起大拇指或向下”的临床试验者转变为能够询问免疫机制的参与并测试有关先天性和适应性免疫的特定假设的人。

Project Summary/Abstract Each year in the US ~500,000 individuals seek care after burn injury, and ~40,000 sustain major thermal burn injury (MThBI) requiring hospitalization. Approximately three-quarters of hospitalized MThBI survivors require skin grafting, a surgical procedure in which skin or another material is applied to the burn injury site (graft site). More than half of individuals who receive a skin grafts develop severe unremitting graft site pain. New non-opioid interventions to improve pain outcomes in MThBI survivors receiving skin graft are urgently needed. Importantly, the scientific community has increasingly recognized that investing millions in traditional RCTs, that provide only a “thumbs up or down” result, is a poor scientific investment. RCTs provide far greater value when (1) interventions have been shown to effectively engage targeted biological mechanisms are tested, and (2) the trial assesses whether hypothesized mechanisms mediate any observed therapeutic effect. During my K12 award, I gained valuable skills and training in the conduct and analysis of traditional randomized controlled trials (RCTs), and experience conducting research in the MThBI population. In addition, data obtained from my pilot intervention trial testing the ability of vitamin D (vit D) to improve MThBI pain outcomes support the safety, feasibility, and exciting potential of this natural product intervention to reduce or prevent chronic pain after MThBI. Vit D is a promising, low-cost, widely available intervention with potent anti-inflammatory and neuroprotective properties. Vit D has been shown to have powerful effects on immune cell populations, and has been demonstrated to improve pain and related outcomes across a range of neuro/inflammatory disorders. This 3-year NCCIH K23 will build upon my K12 training, and will provide me with the necessary skills and experience to conduct a “state-of-the-art” mechanistic trial of vit D in MThBI survivors. Specifically, during the K23 I will learn to apply the latest mass cytometry methods to serial blood samples obtained from RCT participants to evaluate the degree to which increases in circulating vit D levels result in (1) increases in anti-inflammatory monocyte phenotypes and regulatory T cells, and (2) reduction in pro-inflammatory toll-like receptor 4 signaling and effector T-cells (e.g., Th1 and Th17 cells). In addition, I will learn to use advanced statistical methods (elastic net algorithms and multiple parallel mediation models) to evaluate whether these immune cell changes mediate treatment effects, adjusting for any baseline differences in key psychosocial factors. The study of immune mechanisms of chronic pain development is a rich, exciting, burgeoning area of science. Proposed K23 activities are not only ideal for evaluating vit D target engagement and mechanistic hypotheses in MThBI survivors, but will also provide me with an excellent foundation of skills for a career as an NIH-funded chronic pain researcher and clinical trialist. In sum, the skills and training obtained during my 3-year NCCIH K23 will transition me from a “thumbs up or down” clinical trialist to one capable of interrogating engagement of immune mechanisms and testing specific hypotheses regarding innate and adaptive immunity.