Intracellular Therapeutics for Inflammatory Liver Injury

描述（由申请人提供）：酒精性肝病（ALD）在美国约有200万患者，在4年期间死亡率高达65%。我们假设急性或慢性酒精滥用会改变细胞内介质和促炎信号抑制因子之间的稳态平衡。这种信号在肝细胞的基因重编程中达到高潮，表现为促炎和促凋亡介质的表达。我们将研究乙醇如何改变T细胞介导肝炎模型中两个关键细胞内介质，信号换能器和转录激活因子（STAT） 1和3的对立作用。酒精诱导的由STAT1介导的潜在有害（促凋亡）信号和由STAT1介导的有益（抗凋亡）信号之间的不平衡，将使用我们称为细胞内蛋白治疗的新策略来研究，以靶向由过度STAT1激活引起的促炎和促凋亡信号。我们将扩大我们的成功设计和体内递送细胞因子信号的生理性抑制因子到细胞质蛋白，已知可消融巨噬细胞（Kupffer细胞）中的促炎信号，巨噬细胞在酒精相关的炎症性肝损伤中起重要作用。此外，我们已经开发了一种细胞穿透核输入抑制肽，作为一类新型抗炎和抗凋亡药物的原型，它可以抑制促炎细胞因子/趋化因子的产生，防止T细胞或巨噬细胞介导的大量肝脏凋亡/坏死，并降低动物模型中的死亡率。由于这种细胞穿透肽抑制剂靶向负责应激反应转录因子核输入的细胞内接头，我们将分析核输入接头在酒精诱导的肝细胞损伤中的作用。总的来说，我们预计从这些研究中获得的新知识将推进我们的细胞内蛋白治疗概念，以消除酒精加剧的肝脏炎症和细胞凋亡，并有助于开发针对美国约200万ALD患者中快速衰竭肝脏的新疗法。根据整体工作范围，本拨款申请是根据PA-05-074“酒精诱导组织损伤的机制”提交的。

DESCRIPTION (provided by applicant): Alcoholic liver disease (ALD) afflicts an estimated 2 million patients in the US with an astounding 65% mortality rate over a 4 year period. We hypothesize that acute or chronic alcohol abuse alters homeostatic balance that exists between intracellular mediators and suppressors of proinflammatory signaling. This signaling culminates in genetic reprogramming of liver cells manifested by expression of proinflammatory and proapoptotic mediators. We will study how ethanol alters the opposing roles of two key intracellular mediators, signal transducer and activator of transcription (STAT) 1 and 3 in T cell-mediated hepatitis model. The alcohol-induced imbalance between potentially harmful (proapoptotic) signaling mediated by STAT1 and beneficial (anti-apoptotic) signaling mediated by STATS will be studied using our new strategy termed intracellular protein therapy to target proinflammatory and proapoptotic signaling resulting from excessive STAT1 activation. We will expand our successful design and in vivo delivery of physiologic suppressors of cytokine signaling to the cytoplasmic protein known to ablate proinflammatory signaling in macrophages (Kupffer cells) which play a significant role in alcohol-associated inflammatory liver injury. Moreover, we have developed a cell-penetrating nuclear import inhibitory peptide as a prototype of a new class of anti- inflammatory and anti-apoptotic agents which suppresses production of proinflammatory cytokines/chemokines, prevents massive liver apoptosis/necrosis mediated by T cells or macrophages, and reduces mortality rates in animal models. Since this cell-penetrating peptide inhibitor targets intracellular adaptors responsible for nuclear import of stress responsive transcription factors, we will analyze the role of nuclear import adaptors in alcohol-induced injury of liver cells. Cumulatively, we anticipate that the new knowledge gained from these studies will, advance our concept of intracellular protein therapy to extinguish alcohol-exacerbated liver inflammation and apoptosis, and contribute to the development of new therapies for the rapidly failing liver among an estimated 2 million ALD patients in the US. Based on the overall workscope, this grant application is submitted in response to PA-05-074 "Mechanisms of Alcohol-Induced Tissue Injury".