Zinc supplementation in alcoholic cirrhosis

描述（由申请人提供）：这个K23申请将使Matthew Cave医学博士能够实现他成为一名专注于酒精性肝病（ALD）和营养临床和转化研究的独立研究者的目标。Cave博士将进行一项机制研究，评估硫酸锌治疗酒精性肝硬化（AC）患者的效果。Cave博士职业发展计划的亮点包括：(i)获得跨学科研究（i - ms）理学硕士学位，专注于毒理学，临床试验设计和生物统计学，以及（ii）营养学委员会认证（ABPNS）。这些活动将在最近资助的路易斯维尔大学酒精研究中心（P01）进行，并将由一个咨询委员会每季度进行一次监测。据估计，有200万美国人患有ALD，目前还没有FDA批准的药物可以治疗任何阶段的ALD。我们的初步数据证明(i)人类AC患者缺锌，（ii）小鼠模型中补锌改善肝损伤和肝损伤的假设机制。我们的假设是，硫酸锌治疗将导致在人类AC的发生和进展中发挥作用的机制的改善。为了验证这一假设，我们将对30名Child-Pugh a - b AC患者进行随机、双盲、安慰剂对照、“随机”、每天220毫克硫酸锌的机制研究，为期24个月。主要终点是减少(1)血清内毒素血症和(2)体外基础和内毒素刺激的TNF1生成。次要终点是(i)改善血清锌状态，（ii）增加肠道紧密连接，降低渗透性，（iii）改善血清促炎细胞因子谱，（iv）减少氧化应激，改善血清抗氧化状态，(v)减少肝细胞死亡，（vi）减少纤维化，（vii）改善临床状态。这些研究利用最先进的技术在转化方法中发展对潜在的AC新疗法的更好理解。

DESCRIPTION (provided by applicant): This K23 application will enable Matthew Cave, M.D., to achieve his goal of becoming an independent investigator focusing on clinical and translational research in alcoholic liver disease (ALD) and nutrition. Dr. Cave will conduct a mechanistic study evaluating the effects of zinc sulfate therapy in patients with alcoholic cirrhosis (AC). Highlights of Dr. Cave's career development plan include: (i) obtaining a Master of Science degree in Interdisciplinary Studies (I-MS) focusing on toxicology, clinical trial design, and biostatistics, and (ii) board certification in nutrition (ABPNS). These activities will occur in the setting of the recently funded University of Louisville Alcohol Research Center (P01), and will be monitored quarterly by an advisory committee. An estimated two million Americans have ALD, and there are no FDA approved medications for any stage of ALD. Our preliminary data document (i) zinc deficiency in human subjects with AC, and (ii) improvement in liver injury and in postulated mechanisms of liver injury with zinc supplementation in murine models. Our hypothesis is that zinc sulfate therapy will result in improvement in mechanisms postulated to play a role in the development and progression of human AC. To test this hypothesis, we will perform a randomized, double blind, placebo-controlled, "drop in", mechanistic study of zinc sulfate 220 mg daily in 30 subjects with Child-Pugh A-B AC for 24 months. The primary endpoints are reduction in (i) serum endotoxemia and (ii) ex vivo basal and endotoxin-stimulated TNF1 production. Secondary endpoints are (i) improved serum zinc status, (ii) increased intestinal tight junctions with decreased permeability, (iii) improved serum pro-inflammatory cytokine profile, (iv) reduced oxidative stress and improved serum antioxidant status, (v) reduced hepatocyte death, (vi) decreased fibrosis, and (vii) improved clinical status. These studies utilize state- of-the art techniques in a translational approach to develop an enhanced understanding of a potential new therapy for AC. PUBLIC HEALTH RELEVANCE: This K23 application will enable Matthew Cave, M.D., to achieve his goal of becoming an independent investigator focusing on clinical and translational research in alcoholic liver disease (ALD) and nutrition. We will perform a randomized, double blind, placebo-controlled, "drop in", mechanistic study of zinc sulfate 220 mg daily in 30 subjects with Child-Pugh A-B AC for 24 months.