Metabolic Regulation in the Acute Phase

蛋白质分泌是所有细胞的基本功能。它在复合体中的作用尤为突出。 具有激素、神经和免疫系统的多细胞生物体，用于细胞间的通讯。 内质网(ER)，负责处理分泌蛋白质的早期翻译后处理 试图在客户蛋白质的流入和折叠机器的容量之间保持平衡。 这一平衡很容易被客户蛋白质负荷的波动和病理事件扰乱 损害ER功能。因此，内质网应激，这是破坏这种平衡的结果，在低氧期间发生， 营养缺乏或暴露于同型半胱氨酸等内源性毒素。ER压力也可能会 发生在处理大量客户蛋白负荷的分泌细胞中，例如胰岛素中朗格汉斯胰岛中的13个细胞 抵抗力强的人类。响应内质网应激的信号通路统称为未折叠的 蛋白质反应(UPR)，它们通过减少客户蛋白质合成和通过 上调基因，以增加分泌机构处理客户蛋白的能力。在 与此同时，UPR还激活了促进细胞死亡的信号和基因。这样做的长期目标是 项目的目的是了解在普遍定期审议中是什么控制着生存与死亡的决定，并理解 UPR中的信号如何促进分泌能力。我们将重点关注三个具体目标：定义 翻译抑制和恢复在内质网应激和代谢调节中的作用 内质网应激对细胞存活和组织功能的影响 比如大量分泌的肝脏和胰腺。明确PERK信号在生存中的作用 或通过利用与内质网解偶联的条件性激活形式的PERK来抑制内质网应激细胞的死亡 压力。通过研究明确IRE1在分泌器官发育和维持中的作用 具有实验改变的IRE1功能的细胞和组织的分泌和基因表达。更好的 了解普遍定期审议将有助于合理选择疾病治疗干预的目标。 以及与内质网应激相关的病理状态，如糖尿病、缺血和 高同型半胱氨酸血症。操纵细胞分泌能力的工具可能被用来提高 重组蛋白在培养细胞中或在体内用于基因治疗或细胞治疗。

Protein secretion is an essential function in all cells. It plays a particularly prominent role in complex multiceltular organisms with hormonal, neural and immunological systems for intercellular communication. The endoplasmic reticulum (ER), which handles the early post-translational processing of secreted proteins tries to maintain a balance between the influx of client proteins and the capacity of the folding machinery. This equilibrium is easily perturbed by fluctuations in client protein load and by pathological events that impair ER function. Thus ER stress, a consequence of perturbing this equilibrium, occurs during hypoxia, nutrient deprivation or exposure to endogenous toxins such as homocysteine. ER stress is also likely to occur in secretory cells handling heavy client protein loads, such as 13cells in islets of Langerhans in insulin resistant humans. Signaling pathways responsive to ER stress are referred to collectively as the unfolded protein response (UPR) and they protect cells against ER stress by reducing client protein synthesis and by upregulating genes that increase the capacity of the secretory apparatus to process its client proteins. At the same time the UPR also activates signals and genes that promote cell death. The long term goals of this project are to understand what controls the survival versus death decision in the UPR and to understand how signaling in the UPR promotes secretory capacity. We will focus on three specific aims: To define the role of translational repression and recovery in ER stress and metabolic regulation by studying the impact of mutations that impair elF2(_ dephosphorylation on cell survival in ER stress and on the function of tissues such as liver and pancreas that engage in heavy secretion. To define the role of PERK signaling in survival or death of ER stressed cells by utilizing conditionally active forms of PERK that are uncoupled from ER stress. To define the role of IRE1 in development and maintenance of the secretory apparatus by studying secretion and gene expression in cells and tissues with experimentally-altered IRE1 function. A better understanding of the UPR will permit rational selection of targets for therapeutic interventions in diseases and pathological states associated with ER stress such as diabetes mellitus, ischemia and hyperhomocysteinemia. Tools to manipulate cells' secretory capacity may be used to enhance production of recombinant proteins in cultured cells or in gene therapy or cell therapy in vivo.