Discovering Small Molecule Activators of Stress-responsive Signaling

发现应激反应信号传导的小分子激活剂

• 批准号: 10383671
• 负责人: JEFFERY W KELLY
• 金额: $ 60.17万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10383671
• 关键词: ATF6 gene; Abeta synthesis; Age; Aging; Alzheimer' s Disease; Amyloidosis; Animal Model; Animals; Basic Science; Biochemical; Biological; Biological Assay; Biological Availability; Cardiovascular Diseases; Categories; Cell Culture Techniques; Cell model; Cells; Chemicals; Collaborations; Communities; Defect; Development; Diabetes Mellitus; Disease; Disease model; Equilibrium; Etiology; Eye diseases; Funding; Gene Expression Profiling; Genetic Transcription; Goals; Human Genetics; Individual; Maintenance; Mammals; Mediating; Membrane; Modeling; Mus; Neurodegenerative Disorders; Neurons; Parkinson Disease; Pathogenesis; Pathologic; Pathology; Pathway interactions; Pharmaceutical Chemistry; Pharmacology; Phenotype; Physiological; Protein Biosynthesis; Proteins; Proteomics; Reporter; Scientist; Signal Pathway; Signal Transduction; Specificity; Stress; Testing; Therapeutic; Tissues; Toxic effect; Translations; United States National Institutes of Health; abeta oligomer; age related; arm; base; biological adaptation to stress; cytotoxicity; environmental stressor; genetic approach; healthy aging; high throughput screening; human disease; improved; in vivo; miniaturize; mouse model; neurotoxicity; next generation; normal aging; novel; prevent; programs; proteostasis; response; screening; secretory protein; small molecule; stem cell biology; trafficking; translational potential

The maintenance of secreted protein homeostasis, or proteostasis, involves balancing protein biosynthesis, translocation across membranes, folding, degradation, etc., which we hypothesize is critical for healthy aging. Since the demands on secretory compartments to maintain proteostasis change with development, aging, and environmental stresses, mammals evolved the Unfolded Protein Response (UPR) stress-responsive signaling pathway, which transcriptionally adjusts secretory proteostasis network capacity to meet demand. Recent human genetic, chemical biologic, and in vivo evidence shows that activating the protective IRE1/XBP1s or ATF6 arms of the UPR has significant promise to ameliorate age-related declines in secretory proteostasis and correct imbalances associated with etiologically-diverse diseases, including systemic amyloid diseases, cardiovascular disorders, diabetes, and neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. Few compounds exist to achieve arm-selective UPR activation, and those that do suffer from limitations that prevent their translational development. We have leveraged cell-based transcriptional reporter assays miniaturized for high-throughput screening (HTS), along with whole cell transcriptional and proteomic profiling to understand the selectivity of the transcriptional and translational response generated by our screening hits. We have elaborated promising compounds using medicinal chemistry to establish first-in- class small molecule `proteostasis regulators' that selectively activate the protective IRE1/XBP1s or ATF6 signaling arms of the UPR with improved potency and selectivity, and we seek their mechanism of action through multiple approaches. We will assess whether our proteostasis regulators can induce protective, arm- selective UPR activation in young and old animals. We have established collaborations to test the hypothesis that our IRE1/XBP1s and ATF6 activators will be useful for ameliorating pathologic imbalances in secretory proteostasis associated with multiple diseases, including the systemic amyloidoses, degenerative eye diseases, cardiovascular disease, and neurodegenerative disorders. Furthermore, we will show that these compounds pharmacologically ameliorate two pathologic phenotypes associated with Alzheimer's disease in cell culture models: i.e., the pathologic production of Aβ and Aβ oligomer-associated neuronal cytotoxicity. We will deliver to the scientific community the first well-characterized small molecules that preferentially activate the IRE1/XBP1s or the ATF6 UPR transcriptional programs with a defined potency and selectivity. These compounds have the potential to be widely employed as therapeutics for a spectrum of age-associated diseases. Importantly, these compounds will be made available to all scientists with disease models wherein pharmacologic IRE1/XBP1s or ATF6 activation has the potential to influence pathogenesis. The availability of these compounds offers the promise to broadly influence multiple aspects of scientific endeavor funded by the NIH, including basic science such as stem cell biology.

分泌蛋白稳态或蛋白质稳态的维持涉及平衡蛋白质生物合成， 我们开创的跨膜易位、折叠、降解等对于健康衰老至关重要。 由于维持蛋白质稳态的分泌室的需求随着发育、衰老和生长而变化。 环境压力下，哺乳动物进化出了未折叠蛋白反应（UPR）压力反应信号 途径，该途径通过转录调整分泌蛋白稳态网络能力以满足近期需求。 人类遗传、化学生物学和体内证据表明，激活保护性 IRE1/XBP1 或 UPR 的 ATF6 臂对于改善与年龄相关的分泌性蛋白质稳态下降和 纠正与多种病因疾病相关的失衡，包括系统性淀粉样蛋白疾病， 心血管疾病、糖尿病和神经退行性疾病，如阿尔茨海默病和 很少有化合物能够实现手臂选择性 UPR 激活，而那些确实会遭受帕金森病困扰的化合物。 我们利用基于细胞的转录来摆脱阻碍其翻译发展的限制。 用于高通量筛选 (HTS) 的小型化报告基因检测，以及全细胞转录和 蛋白质组分析以了解转录和翻译反应的选择性 我们利用药物化学精心筛选出有前景的化合物，以建立首创。 选择性激活保护性 IRE1/XBP1 或 ATF6 的小分子“蛋白质稳态调节剂” 普遍定期审议的信号臂具有更高的效力和选择性，我们寻求其作用机制 我们将通过多种方法评估我们的蛋白质稳态调节剂是否可以诱导保护性臂力。 我们已经建立了合作来检验这一假设。 我们的 IRE1/XBP1 和 ATF6 激活剂将有助于改善分泌的病理失衡 蛋白质稳态与多种疾病相关，包括系统性淀粉样变性、眼部退化 此外，我们将证明这些疾病。 化合物在药理学上改善与阿尔茨海默病相关的两种病理表型 细胞培养模型：即 Aβ 和 Aβ 寡聚物相关神经元细胞毒性的病理产生。 将向科学界提供第一个特征明确的小分子，这些小分子优先激活 IRE1/XBP1s 或 ATF6 UPR 转录程序具有明确的效力和选择性。 化合物有可能被广泛用作治疗一系列与年龄相关的疾病的药物 重要的是，这些化合物将提供给所有拥有疾病模型的科学家。 药理学 IRE1/XBP1 或 ATF6 激活有可能影响发病机制。 这些化合物有望广泛影响由美国资助的科学事业的多个方面 NIH，包括干细胞生物学等基础科学。

项目成果

Small molecule strategies to harness the unfolded protein response: where do we go from here?

利用未折叠蛋白质反应的小分子策略：我们下一步该何去何从？

• DOI: 10.1074/jbc.rev120.010218
• 发表时间: 2020-09-04
• 期刊: The Journal of Biological Chemistry
• 作者: Julia M. Gr;jean;jean;R. Wiseman
• 通讯作者: R. Wiseman

Defining the Functional Targets of Cap'n'collar Transcription Factors NRF1, NRF2, and NRF3.

定义 Capncollar 转录因子 NRF1、NRF2 和 NRF3 的功能目标。

• 发表时间: 2020-10-21
• 作者: Ibrahim, Lara;Mesgarzadeh, Jaleh;Xu, Ian;Powers, Evan T;Wiseman, R Luke;Bollong, Michael J
• 通讯作者: Bollong, Michael J

Enforced dimerization between XBP1s and ATF6f enhances the protective effects of the UPR in models of neurodegeneration.

XBP1 和 ATF6f 之间的强制二聚化增强了 UPR 在神经退行性变模型中的保护作用。

• DOI: 10.1016/j.ymthe.2021.01.033
• 发表时间: 2021-02-03
• 期刊: Molecular therapy : the journal of the American Society of Gene Therapy
• 作者: René L. Vidal;Denisse Sepúlveda;Paulina Troncoso;Paula García;Constanza Gonzalez;L. Plate;C. Jerez;J. Cánovas;Claudia A. Rivera;Valentina Castillo;M. Cisternas;Sirley Leal;Alexis Martínez;Julia M. Gr;jean;jean;Donzelli Sonia;H. Lashuel;Alberto J. M. Martin;Verónica Latapiat;S. Matus;S. Sardi;R. Wiseman;C. Hetz
• 通讯作者: C. Hetz

Pharmacological activation of ATF6 remodels the proteostasis network to rescue pathogenic GABAA receptors.

ATF6 的药理激活可重塑蛋白质稳态网络，以拯救致病性 GABAA 受体。

• 发表时间: 2022-04-27
• 作者: Wang, Meng;Cotter, Edmund;Wang, Ya;Fu, Xu;Whittsette, Angela L;Lynch, Joseph W;Wiseman, R Luke;Kelly, Jeffery W;Keramidas, Angelo;Mu, Ting
• 通讯作者: Mu, Ting

Insulin-like growth factor 2 (IGF2) protects against Huntington's disease through the extracellular disposal of protein aggregates.

胰岛素样生长因子 2 (IGF2) 通过细胞外蛋白质聚集体的处理来预防亨廷顿病。

• 发表时间: 2020-11
• 影响因子: 12.7
• 作者: García;Troncoso;Wu, Di;Thiruvalluvan, Arun;Cisternas;Henríquez, Daniel R;Plate, Lars;Chana;Saquel, Cristian;Thielen, Peter;Longo, Kenneth A;Geddes, Brad J;Lederkremer, Gerardo Z;Sh
• 通讯作者: Sh