Evaluation of the Effect of Green Tea Polyphenols on IBD

描述（由申请人提供）： 对绿色茶作为改善健康和治疗疾病的试剂的兴趣在外行和科学文献中都有所增加。绿色茶由几种成分组成，大多数研究集中在多酚部分。绿色茶多酚（GrTP）包括（-）-表儿茶素（EC）、（-）-表没食子儿茶素（EGC）、（-）-表儿茶素-3-没食子酸酯（ECG）和（-）-表没食子儿茶素-3-没食子酸酯（EGCG）。其中，EGCG占总多酚含量的40%以上。治疗和预防的益处归因于多酚的有效抗氧化作用，包括降低癌症的风险。GrTP还具有有效的抗炎特性。GrTP已被证明是核因子-κ B（NF-κ B）的有效抑制剂，NF-κ B是控制肠道炎症的关键调节因子。NF-kB的活化可由多种刺激因子诱导，例如促炎细胞因子肿瘤坏死因子-α（TNF-α）或白细胞介素-1（IL-1）、细菌内毒素或氧化应激。在未受刺激的细胞中，NF-kB作为由p65和p50亚基组成的异源二聚体存在，与抑制性蛋白的转运蛋白-kB（IkB）家族的成员结合。NF-kB激活剂通过IkB激酶（IKK）磷酸化IkB N-末端调节结构域中的两个丝氨酸，诱导26 s蛋白体降解IkB。释放的NF-kB易位到细胞核，结合特异性启动子序列，并诱导促炎细胞因子的表达。这些细胞因子在慢性炎症性肠病（IBD）中以高水平表达。IL-1和TNF-α也在正调节环中激活NF-κ B。这可能导致炎症反应的放大。NF-kB似乎在炎症中起重要作用，并且是抗炎治疗的可能靶点。GrTP给药改善了炎症动物模型。本提案的科学部分旨在评估GrTP在人类中的使用。具体目标1将证实GrTP抑制人外周血单核细胞中的NF-κ B活化。具体目标2将评估GrTP在患有静止期IBD的志愿者中的安全性和耐受性，同时定义GrTP的药代动力学和药效学。具体目标3将进一步评估GrTP在IBD受试者中的安全性，同时提供该疗法在活动性溃疡性结肠炎患者中疗效的初步数据。

DESCRIPTION (provided by applicant): Interest in green tea as an agent for improving health and treating disease has increased in both the lay and scientific literature. Green tea consists of several components, with most research focusing on the polyphenol fraction. The green tea polyphenols (GrTP) include (-)-epicatechin (EC), (-)-epigallocatechin (EGC), (-)- epicatechin-3-gatlate (ECG), and (-)-epigallocatechin-3-gallate (EGCG). Of these, EGCG accounts for greater than 40% of the total polyphenol content. Therapeutic and prophylactic benefits have been attributed to the potent anti-oxidant effects of the polyphenols, including reducing the risk of cancer. GrTP also have potent anti-inflammatory properties. GrTP have proven to be potent inhibitors of nuclear factor-kappa B (NF-kB), a key regutatory factor in the control of intestinal inflammation. Activation of NF-kB can be induced by a variety of stimulatory factors, such as the pro-inflammatory cytokines tumor necrosis factor-alpha (TNF-a) or interleukin-1 (IL-1), bacterial endotoxin, or oxidative stress. In unstimulated cells, NF-kB exists as a heterodimer comprised of p65 and p50 subunits, bound to a member of the inhibitor-kB (IkB) family of inhibitory proteins. NF-kB activators induce degradation of IkB by the 26s proteosome, by phosphorylation of two serines in the N-terminal regulatory domain of IkB by IkB kinase (IKK). The liberated NF-kB translocates to the nucleus, binds specific promoter sequences, and induces expression of proinflammatory cytokines. These cytokines are expressed at high levels in chronic inflammatory bowel disease (IBD). IL-1 and TNF-a also activate NF-kB in a positive regulatory loop. This may lead to amplification of the inflammatory response. NF-kB appears to play a significant role in inflammation, and is a likely target for anti-inflammatory therapies. Animal models of inflammation improved with GrTP administration. The scientific portion of this proposal intends to evaluate the use of GrTP in humans. Specific aim 1 will confirm that GrTP inhibit NF-kB activation in human peripheral blood monocytes. Specific aim 2 will evaluate the safety and tolerability of GrTP in volunteers with quiescent IBD, while defining the pharmacokinetics and pharmacodynamics of GrTP. Specific aim 3 will further evaluate the safety of GrTP in subjects with IBD, while providing preliminary data on the efficacy of this therapy in patients with active ulcerative colitis.