Modulators of liver injury

描述(由申请人提供)： 程序性细胞死亡或细胞凋亡途径的改变可能导致一系列肝病，从急性肝炎到终末期肝病。虽然目前还没有有效的治疗方法来治疗这些肝脏疾病，但研究表明，肝损伤后肝实质和体内平衡的恢复首先是由肝细胞的增殖启动的。因此，肝细胞特异性生存调节因子的鉴定和功能描述可能为深入了解肝保护机制提供更好的信息。在肝细胞特异性因子中，胰岛素样生长因子结合蛋白-1(IGFBP1)被认为在肝脏修复和再生过程中发挥作用。虽然IGFBP1基因在再生肝中的表达调控已经得到了广泛的研究，但对IGFBP1的肝脏功能仍知之甚少。在先前旨在研究IGFBP1表达的遗传干扰如何影响体内肝功能的研究中，我们产生了IGFBP1基因敲除小鼠。我们对IGFBP1缺失型小鼠的初步鉴定表明，IGFBP1缺陷型肝脏在凋亡通路中存在先天缺陷。此外，我们还获得了IGFBP1通过调节线粒体凋亡途径在肝脏中作为一种生存因子发挥作用的证据。因此，拟议的应用将使用生化、细胞培养和动物模型系统来阐明IGFBP1与其他关键细胞因子的相互作用，以促进肝细胞对特定应激信号的反应。相关的具体目标将在一个不同的专家团队的指导下实现，该团队在癌症生物学、程序性细胞死亡、肝脏生物学、肝脏病理学和计算结构生物学方面有着良好的研究记录。此外，指导研究将使申请者能够学习最先进的分子实验和建模技术，并有效地过渡到一个独立的研究计划，调查与肝脏代谢和疾病有关的医学相关研究问题。

DESCRIPTION (provided by applicant): Alterations in pathways of programmed cell death, or apoptosis, may lead to a spectrum of liver diseases, ranging from acute hepatitis to end stage liver disease. Although effective therapies are not yet available for most of these liver disorders, studies have demonstrated that the restoration of hepatic parenchyma and homeostasis, following hepatic injury, is first initiated by proliferation of hepatocytes. Thus, the identification and functional delineation of hepatocyte-specific prosurvival modulators may provide a greater insight underlying hepatoprotective mechanisms. Among the hepatocyte-specific factors that have been implicated to play a role during liver repair and regeneration is the Insulin-like Growth Factor Binding Protein-1 (IGFBP1). Although the regulation of IGFBP1 gene expression in the regenerating liver has been extensively studied, the liver functions of IGFBP1 still are poorly understood. In previous studies designed to investigate how genetic disruption of IGFBP1 expression would affect hepatic function in vivo, we generated IGFBP1 knockout mouse. Our initial characterization of the IGFBP1-null mouse suggests that the IGFBP1-deficient liver has a pre-existing defect in apoptotic pathway. Additionally, we have obtained evidence that IGFBP1 functions as a prosurvival factor in the liver by modulating the mitochondrial apoptotic pathway. Thus, the proposed application will use biochemical, cell culture, and animal model systems to elucidate the interaction of IGFBP1 with other critical cellular factors to promote hepatic cell survival in response to particular stress signals. The interrelated specific aims will be performed under the guidance of a diverse team of experts with a strong track record of research in cancer biology, programmed cell death, liver biology, liver pathology, and computational structural biology. Additionally, the mentored research will enable the applicant to learn state-of-the-art molecular experimental and modeling techniques and to effectively transition to an independent research program investigating medically relevant research problems pertaining to liver metabolism and diseases.