Protein Homeostasis and Proteotoxicity Mechanisms

蛋白质稳态和蛋白质毒性机制

基本信息

批准号：
9197706
负责人：
JONATHAN LIN
金额：
$ 33.91万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-02-01 至 2020-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9197706
关键词：
Apoptosis Apoptosis Inhibitor Attenuated Automobile Driving BIR Domain BIRC4 gene Bioinformatics Caspase Cell Death Cell Survival Cells Chronic Complex Coupled Development Disease Down-Regulation Endoplasmic Reticulum Eukaryotic Cell Event Genes Genetic Transcription Heat shock proteins Impairment In Vitro Link Mammalian Cell Measures Membrane Membrane Proteins Messenger RNA MicroRNAs Modeling Modification Molecular Mus Nerve Degeneration Neurodegenerative Disorders Neurons Organelles PERK kinase Pathogenesis Pathologic Pathology Patient Care Phosphotransferases Play Post-Translational Protein Processing Process Protein Family Proteins Regulation Resistance Role Sequence Homology Signal Transduction Signal Transduction Pathway Societies Testing Translations Ubiquitination arm attenuation base endoplasmic reticulum stress experimental study in vivo inhibitor-of-apoptosis protein knock-down misfolded protein mouse model mutant neuron loss overexpression prevent programs protein degradation protein folding protein misfolding proteostasis proteotoxicity public health relevance response survivin transcription factor ubiquitin ligase ubiquitin-protein ligase virtual

项目摘要

DESCRIPTION (provided by applicant): Protein misfolding is linked to the development and pathology of many neurodegenerative diseases. The endoplasmic reticulum (ER) is a membrane-bound organelle essential for the folding of virtually all secreted and membrane proteins in eukaryotic cells. Pathologic events that interfere with ER protein folding cause ER stress. Cells activate the Unfolded Protein Response (UPR) when they are confronted with protein misfolding and ER stress. UPR signaling and chronic ER stress are seen in many neurodegenerative diseases. UPR signaling promotes cell death and pathology by mechanisms that are poorly understood. Studies from many labs have demonstrated that the UPR signal transduction pathway controlled by PRK-like ER Kinase (PERK) plays an important role in driving ER stress-induced cell death. PERK encodes an ER-resident transmembrane kinase with a luminal domain that detects misfolded proteins coupled to a cytosolic kinase domain and initiates a powerful translational and transcriptional program in response to ER stress. PERK activation leads to global translational attenuation. PERK activation concomitantly induces synthesis of transcription factors, including ATF4 and CHOP. Chronic PERK activation or forced over-expression of ATF4 and CHOP trigger cell death. Conversely, Chop-/- mice are partially resistant to ER stress-induced cell death. The mechanisms by which PERK, ATF4, and CHOP trigger apoptosis are poorly understood. We have recently discovered that chronic ER stress down-regulates the Inhibitor of Apoptosis (IAP) protein family through activity of the PERK-ATF4 signaling axis. Loss of IAPs sensitizes cells to ER stress-induced cell death. Based on these findings, we hypothesize that PERK-ATF4 regulation of IAPs determines whether cells succumb to apoptosis in response to chronic ER stress. To test this model and to further decipher the mechanisms by which PERK-ATF4 regulates XIAP and cell death, we propose the following Specific Aims: 1. Determine the mechanisms that regulate IAP proteins during ER stress. 2. Test the roles of IAP-domain family proteins in ER stress-induced neuronal cell death. 3. Determine the roles of PERK-induced miRNAs in regulating Iaps and cell survival in response to ER stress and protein misfolding. In summary, we propose experiments to decipher how PERK and ATF4 regulate the IAP protein family in response to protein misfolding and ER stress. The significance of our studies is that we will decipher molecular mechanisms that directly trigger apoptosis when cells are confronted with chronic ER stress and protein misfolding. These studies will positively impact society and patient care by identifying fundamental mechanisms governing the pathogenesis and progression of neuronal diseases arising from protein misfolding and ER stress, and these mechanisms can then be targeted to prevent cell death and thereby ameliorate disease.

描述（由申请人提供）：蛋白质错误折叠与许多神经退行性疾病的发展和病理学相关。内质网（ER）是真核细胞中几乎所有分泌蛋白和膜蛋白折叠所必需的膜结合细胞器。干扰 ER 蛋白折叠的细胞会在遇到蛋白质错误折叠和 ER 应激以及慢性应激时激活未折叠蛋白反应 (UPR)。许多实验室的研究表明，UPR 信号转导通路在许多神经退行性疾病中发挥着重要作用，但目前对这种机制知之甚少。 PERK 编码一种内质网驻留跨膜激酶，其具有管腔结构域，可检测与胞质激酶结构域偶联的错误折叠蛋白，并启动强大的翻译和转录程序。对 ER 应激的反应导致 PERK 激活同时诱导转录因子的合成，包括 ATF4 和 CHOP 的慢性激活或 ATF4 和 CHOP 的强制过度表达，从而触发细胞死亡。对 ER 应激诱导的细胞死亡具有部分抵抗力我们最近发现慢性 ER 应激的机制尚不清楚。通过 PERK-ATF4 信号轴的活性下调细胞凋亡抑制剂 (IAP) 蛋白家族。IAP 的缺失使细胞对 ER 应激诱导的细胞死亡敏感。基于这些发现，我们发现 PERK-ATF4 对 IAP 的调节决定了细胞凋亡。细胞是否会因慢性 ER 应激而发生凋亡为了测试该模型并进一步破译 PERK-ATF4 的调节机制。 XIAP 和细胞死亡，我们提出以下具体目标： 1. 确定在内质网应激期间调节 IAP 蛋白的机制 2. 测试 IAP 结构域家族蛋白在 ER 应激诱导的神经元细胞死亡中的作用 3. 确定其作用。 PERK 诱导的 miRNA 在调节 IAP 和细胞存活以应对 ER 应激和蛋白质错误折叠方面的研究总之，我们提出了实验来破译 PERK 和 ATF4 如何调节 IAP。我们研究的意义在于，我们将破译当细胞面临慢性内质网应激和蛋白质错误折叠时直接触发细胞凋亡的分子机制。这些研究将通过确定对社会和患者护理产生积极影响。蛋白质错误折叠和内质网应激引起的神经元疾病的发病机制和进展的基本机制，然后可以针对这些机制来预防细胞死亡，从而改善疾病。