Defining CHOP-10 Dependent Adaptive ER Stress Pathways in Neurons

定义神经元中的 CHOP-10 依赖性自适应 ER 应激通路

• 批准号: 9097826
• 负责人: Laura Yunes-Medina
• 金额: $ 4.26万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-01 至 2017-07-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9097826
• 关键词: Adult; Apoptosis; Apoptotic; Architecture; Area; Brain; Brain-Derived Neurotrophic Factor; Cell physiology; Cerebral Ischemia; Cessation of life; Coculture Techniques; Complex; Computer Simulation; Coupling; Data; Development; Disease; Drug Targeting; Endoplasmic Reticulum; Equilibrium; Failure; Gene Expression; Genes; Genetic Transcription; Glutamates; Health; Heart Arrest; Hippocampus (Brain); In Vitro; Injection of therapeutic agent; Injury; Ischemia; Ischemic Brain Injury; Lentivirus Vector; Life; Link; Mediating; Metabolic stress; Microfluidics; Modeling; Molecular; Mutate; Nervous system structure; Neurites; Neurological outcome; Neuronal Plasticity; Neurons; Nuclear; Pathway interactions; Patients; Pharmaceutical Preparations; Phosphorylation; Phosphotransferases; Play; Post-Translational Protein Processing; Protein Biosynthesis; Proteins; Resistance development; Role; Signal Transduction; Signal Transduction Pathway; Site; Stress; Stroke; Testing; Therapeutic; Toxic effect; Transcript; Translations; United States; axon injury; base; biological adaptation to stress; endoplasmic reticulum stress; genetic approach; in vitro Model; in vivo; mouse model; mutant; neuron loss; neurotrophic factor; next generation sequencing; novel; preconditioning; research study; response; sensor; therapy design; treatment strategy

DESCRIPTION (provided by applicant): De novo gene expression induced by endoplasmic reticulum (ER) stress plays a decisive role in determining whether neurons live or die following global cerebral ischemia. However, the molecular mechanisms regulating the balance between protective and damaging responses originating from the ER remain unsettled. We discovered that the ER-stress factor CHOP-10, previously linked to differentiation and apoptosis, induces ischemic tolerance in cortical neurons and is activated by the potent neuroprotective brain derived neurotrophic factor (BDNF). Importantly, we also found that loss of CHOP-10 expression alters neuritic responses to ischemia in the adult hippocampus. These results suggest that CHOP-10 plays a more complex role in the neuronal response to ischemic injury that previously recognized. In this proposal we test the hypothesis that CHOP functions as an integrator of both adaptive and pathological responses. Preliminary studies reveal that post-translational modifications induced by PKC and related kinase pathways have marked effects on the stability, localization and toxicity of CHOP-10. Using in vitro culture models and the 3-vessel occlusion model of transient global ischemia, we will define the mechanism(s) and role of BDNF-CHOP coupling. Together, these experiments seek to broaden our understanding regarding the role of CHOP-10 and ER stress responses in ischemic brain injury, and identify the molecular basis for ER-stress dependent transcriptional switching. Since CHOP itself is not a typical drug target, our focus on CHOP-kinase pathways may have important translational implications. The identification of suitable targets in this network could serve as the basis for therapies designed to inhibit delayed neuronal loss after ischemic brain injury.

描述（申请人提供）：内质网（ER）应激诱导的从头基因表达在确定全脑缺血后神经元的存活或死亡中起着决定性作用。然而，调节源自内质网的保护性反应和破坏性反应之间平衡的分子机制仍然不稳定。我们发现，先前与分化和细胞凋亡相关的内质网应激因子 CHOP-10 可诱导皮质神经元的缺血耐受性，并被有效的神经保护性脑源性神经营养因子 (BDNF) 激活。重要的是，我们还发现 CHOP-10 表达的丧失会改变成人海马对缺血的神经炎反应。这些结果表明，CHOP-10 在神经元对缺血性损伤的反应中发挥着先前认识到的更复杂的作用。在本提案中，我们测试了 CHOP 作为适应性反应和病理反应的整合器的假设。初步研究表明，PKC和相关激酶途径诱导的翻译后修饰对CHOP-10的稳定性、定位和毒性具有显着影响。使用体外培养模型和短暂性全局缺血的 3 血管闭塞模型，我们将定义 BDNF-CHOP 耦合的机制和作用。总之，这些实验旨在扩大我们对 CHOP-10 和 ER 应激反应在缺血性脑损伤中的作用的理解，并确定 ER 应激依赖性转录转换的分子基础。由于 CHOP 本身不是典型的药物靶点，因此我们对 CHOP 激酶途径的关注可能具有重要的转化意义。该网络中合适靶点的识别可以作为旨在抑制缺血性脑损伤后迟发性神经元丢失的治疗的基础。