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: 9904304
• 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/9904304
• 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; Structure; Testing; Therapeutic; Tissues; Toxic effect; Translations; United States National Institutes of Health; abeta oligomer; age related; arm; base; biological adaptation to stress; cytotoxicity; 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

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.

分泌蛋白质稳态或蛋白质稳态的维持涉及平衡蛋白质生物合成， 跨膜转运、折叠、降解等，我们假设这对健康老龄化至关重要。 由于对分泌区室维持蛋白质稳态的需求随着发育、衰老和衰老而变化， 环境胁迫下，哺乳动物进化出未折叠蛋白反应（UPR）应激反应信号 途径，转录调节分泌蛋白质稳态网络的能力，以满足需求。最近 人类遗传学、化学生物学和体内证据表明，激活保护性IRE 1/XBP 1或 UPR的ATF 6臂具有显著改善分泌性蛋白质稳态的年龄相关性下降的前景， 纠正与病因多样性疾病相关的失衡，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， 帕金森氏症。很少有化合物能够实现臂选择性UPR激活， 从阻止其转化发展的限制中解放出来。我们利用了细胞转录 报告基因测定小型化，用于高通量筛选（HTS），沿着全细胞转录和 蛋白质组分析，以了解转录和翻译反应的选择性产生的 我们的筛选结果我们已经详细阐述了有前途的化合物使用药物化学，以建立第一次在 类小分子“蛋白质稳态调节剂”，选择性激活保护性IRE 1/XBP 1或ATF 6 具有改进的效力和选择性的UPR的信号臂，我们寻求它们的作用机制 通过多种途径。我们将评估我们的蛋白质稳态调节剂是否能诱导保护性的，手臂- 在年轻和年老的动物中选择性UPR激活。我们已经建立了合作关系来验证这个假设 我们的IRE 1/XBP 1和ATF 6激活剂将有助于改善分泌失调的病理性失衡， 与多种疾病相关的蛋白质稳态，包括系统性淀粉样变性、退行性眼 疾病、心血管疾病和神经退行性疾病。此外，我们将证明，这些 化合物可改善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寡聚体相关神经元细胞毒性的病理产生。我们 将向科学界提供第一个具有良好特征的小分子， IRE 1/XBP 1或ATF 6 UPR转录程序具有确定的效力和选择性。这些 化合物具有广泛用作一系列与年龄相关的疾病的治疗剂的潜力， 疾病重要的是，这些化合物将提供给所有具有疾病模型的科学家，其中 药理学IRE 1/XBP 1或ATF 6活化具有影响发病机制的潜力。的可用性 这些化合物提供了广泛影响科学奋进的多个方面的希望， NIH，包括干细胞生物学等基础科学。