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：
8886877
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/8886877
关键词：
Apoptosis Apoptosis Inhibitor Attenuated Automobile Driving BIR Domain BIRC4 gene Binding Bioinformatics Caspase Cell Death Cell Survival Cells Chronic Complex Coupled Development Disease Down-Regulation Endoplasmic Reticulum Eukaryotic Cell Event Genes Heat shock proteins Homeostasis 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 X-linked IAP arm attenuation base endoplasmic reticulum stress in vivo inhibitor-of-apoptosis protein knock-down mouse model mutant neuron loss prevent programs protein degradation protein folding protein misfolding public health relevance research study response stress protein survivin transcription factor ubiquitin ligase ubiquitin-protein ligase

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（由适用提供）：蛋白质错误折叠与许多神经退行性疾病的发育和病理有关。内质网（ER）是膜结合的有机物，对于真核细胞中几乎所有分泌和膜蛋白的折叠至关重要。干扰ER蛋白质折叠的病理事件会导致ER应力。当细胞遇到蛋白质错误折叠和ER应激时，激活了未折叠的蛋白质反应（UPR）。在许多神经退行性疾病中都可以看到UPR信号传导和慢性ER应激。 UPR信号传导通过知之甚少的机制促进细胞死亡和病理。来自许多实验室的研究表明，由PRK样ER激酶（PERK）控制的UPR信号转移途径在驱动ER应力诱导的细胞死亡方面起着重要作用。 PERK编码具有Luminal结构域的ER居民跨膜激酶，该域检测到与胞质激酶结构域耦合的错误折叠的蛋白质，并启动强大的翻译和转录程序，以响应ER应力。 PERK激活导致全球翻译衰减。 PERK激活同时诱导转录因子的合成，包括ATF4和CHOP。慢性PERK激活或强迫ATF4和CHOP触发细胞死亡的过度表达。相反，CHOP - / - 小鼠对ER应力诱导的细胞死亡具有部分抗性。 perk，atf4和cop触发凋亡的机制知之甚少。我们最近发现，慢性ER应力通过PERK-ATF4信号轴的活性下调凋亡（IAP）蛋白质的抑制剂。 IAPS感官细胞因ER应力诱导的细胞死亡而丧失。基于这些发现，我们假设PERK-ATF4 IAPS的调节决定了细胞是否响应慢性ER应激而屈服于凋亡。为了测试该模型，并进一步破译了PERK-ATF4调节XIAP和细胞死亡的机制，我们提出了以下特定目的：1。确定在ER应力期间调节IAP蛋白的机制。 2。测试IAP-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PERK诱导的miRNA在响应ER应激和蛋白质错误折叠时确定IAP和细胞存活中的作用。总而言之，我们提出了实验，以破译perk和atf4如何响应蛋白质折叠和ER应激而调节IAP蛋白质家族。我们研究的意义在于，当细胞面临慢性ER应激和蛋白质错误折叠时，我们将破译直接触发凋亡的分子机制。这些研究将通过鉴定管理蛋白质错误折叠和ER压力引起的神经元疾病的发病机理和进展的基本机制，从而对社会和患者护理产生积极影响，然后可以针对这些机制来防止细胞死亡，从而改善疾病。