Defining Neurotherapeutic Targets in Hypoxia-Induced CHOP-10 Signaling Networks

定义缺氧诱导的 CHOP-10 信号网络中的神经治疗靶点

• 批准号: 8243634
• 负责人: MARC W HALTERMAN
• 金额: $ 23.7万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8243634
• 关键词: Acute; Address; Anoxic Encephalopathy; Apoptosis; Apoptotic; Area; Behavior; Belief; Biological; Biology; Brain-Derived Neurotrophic Factor; Cell Death; Cells; Cessation of life; Clinical Trials; Complement; Cues; Data; Development; Disease; Dominant-Negative Mutation; Drug Delivery Systems; Endoplasmic Reticulum; Epitopes; Event; Exhibits; Family; Gene Expression; Gene Targeting; Genetic; Heart Arrest; Heterodimerization; Hour; Human; Hypoxia; Image; In Vitro; Injury; Intervention; Intravenous; Ischemia; Knock-out; Link; Measures; Mediating; Modeling; Molecular Genetics; Molecular Target; Mus; Necrosis; Neurons; Neuroprotective Agents; Output; Patients; Phase; Physiological; Play; Post-Translational Protein Processing; Process; Property; Proteins; Protocols documentation; Publishing; RNA Interference; Role; Severities; Signal Pathway; Signal Transduction; Site-Directed Mutagenesis; Societies; Stimulus; Stress; Stroke; Testing; Therapeutic; Toxic effect; Update; Viral; activating transcription factor; base; brain tissue; economic impact; endoplasmic reticulum stress; environmental change; gene complementation; improved; in vivo; interest; mutant; neuron loss; neuroprotection; novel; programs; response; thrombolysis; tool; transcription factor

Stroke places a significant burden on our patients and their families, and has a major economic impact on society. While advances in the areas of revascularization have improved our ability to treat this devastating disorder, the development of neuroprotective drugs targeting the delayed neuron loss has not kept a pace. Protective strategies that target the acute phase of necrotic cell loss after stroke have failed in clinical trials. Our belief, which is supported by evidence from imaging data in humans, is that these Interventions fail to address the wave of neuronal cell death that matures during the hours to days after the inciting stimulus. We seek to identify new molecular targets and therapies that can alter transcriptional responses in endangered brain tissue, which without intervention Is destined to die. We envision that therapies based on our discoveries would complement Intravenous or Intra-arterial thrombolysis protocols after focal stroke, and In patients who have sustained global anoxic brain injury after cardiac arrest. Hypoxia is a key physiologic component of stroke, and our studies indicate that the endoplasmic reticulum (ER) plays a major role in stimulating de novo adaptive and pathological gene expression in neurons. We have identified a cluster of bZIP transcription factors that are activated in other paradigms involving ER stress. One factor of particular Interest is the protein Chop-10 (ddit3/gadd153). While most published studies indicate Chop serves a pathological role, our data suggests Chop promotes adaptive signaling In the face of hypoxic challenge. We also find that Chop is subject to post-translational modification (PTM), and that Chop may tie required for BDNF induced neuroprotection. In this updated ROO proposal we focus on understanding the factors governing Chop's ability to either protect or trigger cell death programs in neurons. Discoveries made during the K99 phase have led us to define the upstream signals linking BDNF mediated protection with Chop activation. These studies buikj upon progress made during the K99 phase and use a variety of molecular genetic tools to study Chop-10 biology in stroke-relevant experimental paradigms. We anticipate that our results will aid in the identification of novel and tractable therapeutics for stroke.

中风给我们的患者及其家庭带来了沉重的负担，并对他们的经济产生了重大影响。 社会虽然血运重建领域的进展提高了我们治疗这种毁灭性疾病的能力， 然而，针对延迟性神经元丢失的神经保护药物的开发并没有跟上步伐。 针对中风后坏死细胞丢失的急性期的保护策略在临床试验中失败了。 我们的信念得到了人类成像数据证据的支持，即这些干预措施未能 解决在刺激后数小时至数天内成熟的神经元细胞死亡的浪潮。我们 寻求确定新的分子靶点和疗法，可以改变濒危物种的转录反应， 脑组织，如果不进行干预，它注定会死亡.我们设想，基于我们的 这些发现将补充局灶性卒中后的静脉或动脉溶栓方案， 心脏骤停后持续性全脑缺氧性脑损伤的患者。 缺氧是中风的一个重要生理因素，我们的研究表明， 内质网（ER）在刺激新生适应性和病理性基因表达中起主要作用， 神经元我们已经确定了一组bZIP转录因子，它们在其他范例中被激活。 包括内质网应激一个特别感兴趣的因子是蛋白质Chop-10（ddit 3/gadd 153）。虽然大多数 已发表的研究表明Chop具有病理作用，我们的数据表明Chop促进适应性 在面对缺氧挑战时发出信号。我们还发现，Chop受翻译后 Chop可能是BDNF诱导的神经保护所必需的。在此更新的ROO中 我们的建议集中在理解Chop保护或触发细胞死亡的能力的因素上 神经元中的程序。在K99阶段的发现使我们定义了上行信号 将BDNF介导的保护与Chop激活联系起来。这些研究建立在 K99期，并利用多种分子遗传学工具研究Chop-10生物学在脑卒中相关 实验范例我们预计，我们的研究结果将有助于确定新的和易处理的 中风的治疗方法