Molecular adn Chemical Biology of Integrated ER Stre

综合内质网应激的分子与化学生物学

• 批准号: 7843520
• 负责人: BERTAL H. AKTAS
• 金额: $ 17.37万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-15 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7843520
• 关键词: 5' Untranslated Regions; Alzheimer' s Disease; Antibodies; Biogenesis; Biological Assay; Biology; Cells; Chaperone Gene; Chemical Agents; Chemical Modifier; Chemicals; Chemistry; Chronic; Code; Collection; Complex; Development; Disease; Dose; Endoplasmic Reticulum; Eukaryotic Initiation Factors; Firefly Luciferases; Functional disorder; Future; Gene Mutation; Genes; Genetic; Genetic Screening; Goals; Homeostasis; Human; In Vitro; Inflammation; Institutes; Introns; Lead; Luciferases; Malignant Neoplasms; Mediating; Messenger RNA; Molecular; Molecular Genetics; Monitor; Neurodegenerative Disorders; Nucleotides; PERK kinase; Parkinson Disease; Pathogenesis; Pharmacologic Substance; Phosphorylation; Physiological; Physiology; Play; Protein Biosynthesis; Protein Isoforms; Proteins; RNA Splicing; RNA library; Renilla Luciferases; Reporter; Role; Route; Screening procedure; Signal Pathway; Site; Small Interfering RNA; Stimulus; Stress; Structure; Time; Translation Initiation; Translations; Tunicamycin; Untranslated Regions; Up-Regulation; Western Blotting; activating transcription factor 4; arm; base; biological adaptation to stress; chemical genetics; endoplasmic reticulum stress; high throughput screening; human disease; in vivo; knock-down; novel therapeutics; positional cloning; public health relevance; response; small molecule libraries; transcription factor; type I and type II diabetes

DESCRIPTION (provided by applicant): The ultimate goal of this application is the development chemical and genetic probes by high throughput screening assays for the study of endoplasmic reticulum (ER) biology and elucidating the role of the integrated ER-stress response in the pathogenesis human diseases. The Endoplasmic reticulum (ER) is the site of folding and assembly for most proteins destined for secretion or sub-cellular compartments. Reverse genetic studies indicate that abrogation of the integrated ER-stress response is lethal. ER homeostasis is therefore highly regulated and the demand for protein synthesis and the capacity of ER to fold the newly synthesized proteins must be matched. Any mismatch between the folding capacity of the ER and the demand for new proteins causes the accumulation of unfolded proteins in the ER and triggers the integrated ER-stress response, which attempts to correct the imbalance by one of three distinct, but integrated routes. Disorders of integrated ER-stress response are implicated in the pathogenesis of many malignancies, including type I and type II diabetes, cancer, inflammation, and neurodegenerative disorders. Despite this importance and the broad spectrum of malignancies associated with disorders of integrated ER-stress response, neither the chemical nor molecular genetics of the integrated ER-stress response have been studied in a systematic manner. We therefore propose to identify chemical and genetic modifiers of integrated ER stress response, which will enable in vitro and in vivo studies of the ER, and will serve as a future platform for the development of pharmaceutical agents for the therapy of human disorders in which disregulation of integrated ER-stress response is implicated. We therefore propose to take advantage of our recently developed high throughput screening (HTS) assays, which interrogate different arms of the integrated ER-stress response. Specifically we will screen libraries of chemical collections and small interfering RNAs (siRNA) to identify chemical probes and siRNAs that modify three distinct arms of integrated ER-stress response. The chemical and genetic modifiers of integrated ER-stress response will be validated in secondary and counter assays. The chemical probes identified through this effort will be critical for elucidating the role of ER-stress in the normal physiology as well as in the genesis of malignancies in which perturbations of ER- homeostasis are implicated. These probes may also serve as lead compounds for the development of ER-stress modifiers for the treatment of human disorders. Similarly, the genetic modifiers of integrated ER stress identified through this effort ma b targets for the development of novel therapeutics. PUBLIC HEALTH RELEVANCE: Mismatch between the folding capacity of the ER and demand for folding new proteins causes accumulation of unfolded proteins in the ER which then triggers integrated ER-stress response to restore the ER-homeostais. Various physiological and pathological stimuli as well as genetic mutations or other aberrations that compromise the integrated ER-stress response are associated with or implicated in the pathogenesis of many malignancies including type I and type II diabetes, inflammation, and neurodegenerative disorders including Alzheimer's and Parkinson's disease. Despite the importance of integrated ER-stress response in the pathophysiology of many disorders, there are very few chemical and genetic modifiers of the integrated ER-stress response, that we propose to remedy by screening chemical and siRNA libraries in high throughput integrated ER-stress response assay we have developed.

描述（由申请人提供）：本申请的最终目标是通过高通量筛选试验开发化学和遗传探针，用于研究内质网（ER）生物学，并阐明整合的 ER 应激反应在人类发病机制中的作用。疾病。内质网 (ER) 是大多数用于分泌或亚细胞区室的蛋白质的折叠和组装位点。反向遗传学研究表明，废除整合的内质网应激反应是致命的。因此，内质网稳态受到高度调节，蛋白质合成的需求和内质网折叠新合成蛋白质的能力必须相匹配。内质网折叠能力与新蛋白质需求之间的任何不匹配都会导致内质网中未折叠蛋白质的积累，并触发整合的内质网应激反应，该反应试图通过三种不同但整合的途径之一来纠正这种不平衡。内质网应激综合反应紊乱与许多恶性肿瘤的发病机制有关，包括 I 型和 II 型糖尿病、癌症、炎症和神经退行性疾病。尽管这种重要性以及与整合内质网应激反应疾病相关的广泛的恶性肿瘤，但整合内质网应激反应的化学和分子遗传学都尚未得到系统的研究。因此，我们建议鉴定综合 ER 应激反应的化学和遗传修饰剂，这将使 ER 的体外和体内研究成为可能，并将作为开发用于治疗人类疾病的药物制剂的未来平台。涉及综合 ER 应激反应。因此，我们建议利用我们最近开发的高通量筛选（HTS）测定法，该测定法询问综合内质网应激反应的不同部分。具体来说，我们将筛选化学集合和小干扰 RNA (siRNA) 文库，以鉴定可修饰整合 ER 应激反应的三个不同臂的化学探针和 siRNA。综合内质网应激反应的化学和遗传修饰剂将在二次和反分析中得到验证。通过这项工作鉴定的化学探针对于阐明内质网应激在正常生理学以及与内质网稳态扰动有关的恶性肿瘤的发生中的作用至关重要。这些探针还可以作为开发用于治疗人类疾病的内质网应激调节剂的先导化合物。同样，通过这项工作确定的整合内质网应激的遗传修饰剂可能是开发新疗法的目标。公共健康相关性：内质网折叠能力与折叠新蛋白质的需求之间的不匹配会导致内质网中未折叠蛋白质的积累，然后触发综合内质网应激反应以恢复内质网稳态。各种生理和病理刺激以及损害综合内质网应激反应的基因突变或其他畸变与许多恶性肿瘤的发病机制相关或牵涉其中，包括 I 型和 II 型糖尿病、炎症和神经退行性疾病，包括阿尔茨海默病和帕金森病。尽管整合 ER 应激反应在许多疾病的病理生理学中很重要，但整合 ER 应激反应的化学和遗传修饰剂非常少，我们建议通过筛选高通量整合 ER 应激中的化学和 siRNA 文库来弥补我们开发了反应测定法。

项目成果

In vitro inhibition of translation initiation by N,N'-diarylureas--potential anti-cancer agents.

• DOI: 10.1016/j.bmcl.2011.10.126
• 发表时间: 2012-01-01
• 期刊: Bioorganic & medicinal chemistry letters
• 影响因子: 2.7
• 作者: Denoyelle, Severine;Chen, Ting;Chen, Limo;Wang, Yibo;Klosi, Edvin;Halperin, Jose A.;Aktas, Bertal H.;Chorev, Michael
• 通讯作者: Chorev, Michael

eIF2α Phosphorylation Mediates IL24-Induced Apoptosis through Inhibition of Translation.

eIF2α 磷酸化通过抑制翻译介导 IL24 诱导的细胞凋亡。

• 发表时间: 2017-08
• 作者: Persaud, Leah;Zhong, Xuelin;Alvarado, Giselle;Do, Winchie;Dejoie, Jordan;Zybtseva, Anna;Aktas, Bertal Huseyin;Sauane, Moira
• 通讯作者: Sauane, Moira

Dual activators of protein kinase R (PKR) and protein kinase R-like kinase PERK identify common and divergent catalytic targets.

蛋白激酶 R (PKR) 和蛋白激酶 R 样激酶 PERK 的双重激活剂可识别常见和不同的催化靶点。

• 发表时间: 2013-07-08
• 作者: Bai, Huijun;Chen, Ting;Ming, Jie;Sun, Hong;Cao, Peng;Fusco, Dahlene N;Chung, Raymond T;Chorev, Michael;Jin, Qi;Aktas, Bertal H
• 通讯作者: Aktas, Bertal H