Role of the Unfolded Protein Response in Beta Cell

描述（由申请人提供）：糖尿病是世界范围内发病率和死亡率的主要原因，与细胞功能紊乱有关，导致葡萄糖刺激的胰岛素分泌丧失，以控制血糖。最近的研究表明，细胞功能和/或存活与一种称为未折叠蛋白反应（UPR）的细胞内信号通路有关。当未折叠蛋白在内质网（ER）的管腔内积累时，三个UPR信号转导亚通路被激活，以增加蛋白质折叠能力和增加蛋白质降解机制。通过perk介导的真核翻译起始因子2 (elF2a) α亚基的磷酸化（UPR的一个亚途径），蛋白质合成会短暂减弱。最近，我们发现PERK/elFa信号是维持内质网环境以支持血糖升高时高水平胰岛素产生所必需的。我们的发现支持了胰岛素产生的增加超过内质网蛋白质折叠能力的假设。在这些条件下，PERK/elF2a亚通路被短暂激活以防止氧化应激，当永久激活时，通过诱导转录因子CHOP诱导细胞死亡反应。我们提出减少氧化应激或阻止CHOP表达将改善胰岛素抵抗的细胞功能和存活。鉴于PERK/elF2a UPR亚通路在细胞功能中的重要性，IRE1和ATF6 UPR亚通路是否也可能对细胞功能至关重要？提出的研究将阐明PERK/elF2a， IRE1和ATF6信号的要求，使用新的遗传小鼠模型，其中UPR传感器基因可以以时间和/或组织特异性的方式“打开”或“关闭”。这些体内模型将用于阐明对细胞衰竭的新见解，并评估治疗干预的新模式。糖尿病是一种多因素疾病，主要源于胰腺细胞不能产生足够数量的胰岛素来控制血糖水平。过量的胰岛素合成可导致细胞内未折叠蛋白的积累。对未折叠蛋白激活的细胞信号通路的研究将有助于对这种疾病的认识和新的治疗方法。

DESCRIPTION (provided by applicant): Diabetes is a world-wide major cause of morbidity and mortality that is associated with disturbances in ¿ cell function that result in the loss of glucose-stimulated insulin secretion for control of blood glucose. Recent studies demonstrated an association between ¿ cell function and/or survival with an intracellular signaling pathway termed the unfolded protein response (UPR). Upon accumulation of unfolded proteins in the lumen of the endoplasmic reticulum (ER), three UPR signal transduction subpathways are activated to increase the protein folding capacity and increase the protein degradative machinery. Protein synthesis is transiently attenuated through PERK-mediated phosphorylation of the alpha subunit of eukaryotic translation initiation factor 2 (elF2a), one subpathway of the UPR. Recently, we discovered that PERK/elFa signaling is required to preserve the environment of the ER to support high-level insulin production in response to increases in blood glucose. Our discoveries support the hypothesis that increases in insulin production exceed the protein-folding capacity of the ER. Under these conditions, the PERK/elF2a subpathway is activated transiently to prevent oxidative stress, and when perpetually activated, induces a cell death response through induction of the transcription factor CHOP. We propose that reducing oxidative stress or preventing CHOP expression will improve ¿ cell function and survival in response to insulin resistance. Given the significance of the PERK/elF2a UPR subpathway in ¿ cell function, is it likely that IRE1 and ATF6 UPR subpathways are also essential for ¿ cell function. The studies proposed will elucidate the requirements of PERK/elF2a, IRE1, and ATF6 signaling using novel genetic mouse models in which UPR sensor genes can be turned 'on' or 'off' in a temporal- and/or tissue-specific manner. These in vivo models will be used to elucidate novel insights into ¿ cell failure and to evaluate novel modalities for therapeutic intervention. Diabetes is a multifactorial disease that stems largely from an inability of pancreatic ¿ cells to produce adequate amounts of insulin for control of blood glucose levels. Excessive insulin synthesis can lead to accumulation of unfolded protein within the ¿ cell. The study of cell signaling pathways activated by unfolded protein will lead to insights and new treatments for this disease.