Peptide therapy for alcohol-induced CNS injury

肽疗法治疗酒精引起的中枢神经系统损伤

• 批准号: 10572298
• 负责人: Mohammed Abdul Muneer
• 金额: $ 25.46万
• 依托单位: HACKENSACK UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10572298
• 关键词: ATF2 gene; Alcohol abuse; Alcohol consumption; Alcohol-Induced Disorders; Alcohols; Alzheimer' s Disease; Amyotrophic Lateral Sclerosis; Animals; Anti-Inflammatory Agents; Antioxidants; Anxiety; Apoptotic; Behavioral; Binding Sites; Biochemical; Blood - brain barrier anatomy; Brain; Brain Injuries; Cell Death; Cells; Cerebellum; ChIP-seq; Chronic; Chronic Disease; Clinical; Cognitive; Cognitive deficits; Cytoprotection; Darkness; Data; Defense Mechanisms; Disease; Drug Metabolic Detoxication; Feedback; Free Radicals; Functional disorder; Gene Expression; Gene Proteins; Genes; Genetic Transcription; Goals; Heavy Drinking; Hippocampus; Impairment; Inflammatory; Injections; Investigation; Knock-out; Knockout Mice; Knowledge; Light; Matrix Metalloproteinases; Mediating; Memory; Memory impairment; Mental Depression; Motor; Multiple Sclerosis; Mus; Nerve Degeneration; Nervous System Trauma; Neurocognitive Deficit; Neurologic; Neurologic Deficit; Nuclear; Nuclear Translocation; Nucleic Acid Regulatory Sequences; Oxidants; Oxidative Stress; Oxidative Stress Induction; Parkinson Disease; Pathway interactions; Penetration; Peptides; Prefrontal Cortex; Proteins; Psychological Stress; Publishing; Recovery; Recovery of Function; Regulation; Reporting; Research Personnel; Resistance; Response Elements; Role; Sensory; Signal Pathway; Signal Transduction; Stroke; Sucrose; System; Testing; Therapeutic; Therapeutic Agents; Therapeutic Intervention; Toxic effect; Transcription Coactivator; Transforming Growth Factors; Traumatic Brain Injury; United States; Up-Regulation; Work; alcohol effect; alcohol exposure; antioxidant enzyme; behavior test; central nervous system injury; clinically relevant; cognitive function; cohort; drug of abuse; gene interaction; in vivo; neural; neuroinflammation; neuron loss; neuropathology; neuroprotection; new therapeutic target; novel; oxidative damage; preference; prevent; problem drinker; psychologic; remediation; repaired; response; subcutaneous; therapeutic target; transcription factor

ABSTRACT Alcohol is the most used and abused drug in the United States. Chronic alcohol abuse results in neuronal degeneration and functional deficits in sensorimotor, memory, psychological, and cognitive functions. We and others have demonstrated that oxidative signaling is the central mechanism in alcohol-induced injury that leads to neurological and functional deficits. Remediation of accumulating oxidative radicals may serve as an effective strategy for preventing the progression of neurological damage in alcoholics. Thus, this proposal will study a novel hypothesis that the brain injury and associated neuroinflammation and neurodegeneration caused by alcohol-induced oxidative damage can be repaired by activating the antioxidant signaling Nrf2 (nuclear factor E2-related factor 2) pathway. The Nrf2 transcriptional system is an endogenous defense mechanism that boosts the expression of many detoxifying, cytoprotective and anti-inflammatory genes by interacting with the antioxidant response element (ARE) in their regulatory regions. Nrf2 has the potential to be a novel and therapeutic target to mitigate alcohol-induced neural damage. Our central hypothesis is that activation of antioxidant-promoting transcription factor Nrf2 alleviates oxidative stress-induced pathophysiological changes associated with excessive alcohol ingestion. These changes include activation of transforming growth factor β1 (TGF-β1) and matrix metalloproteinases (MMPs), neuroinflammatory responses, and neurodegeneration. Activation of Nrf2 transcription factor and up-regulation of endogenous antioxidant enzymes will be achieved by treating animals with Nrf2 activator III TAT peptide (Nrf2 peptide). We will administer Nrf2 peptide to the alcohol ingested mice systemically (subcutaneous) and evaluate its therapeutic potential in alleviating alcohol-associated neurological impairments in defined regions such as the prefrontal cortex, hippocampus, and cerebellum. The proposed study not only validates the cause and effect of Nrf2 peptide in mitigating oxidative stress in AUD but also identifies the mechanistic regulation of Nrf2 transcription factor activated antioxidant genes and their interactions with Nrf2 by ChIP-qPCR, and ChIP-Seq. The protective role of Nrf2 will be determined by assessing its effects on gene expression and protein levels of the major antioxidant, inflammatory, and apoptotic proteins. We will validate the effect of Nrf2 peptide in Nrf2 knock-out (KO) mice (Nrf2−/−). We will also use a cohort of behavioral tests that will utilize to assess cognitive, sensory-motor feedback, and psychological behavioral recovery associated with Nrf2 peptide treatment following alcohol exposure in wild type and Nrf2-/- mice. We will compare the results with control peptide (random sequence with TAT) treated animals. We anticipate that the findings from this study will have extensive clinical relevance.

摘要 酒精是美国使用和滥用最多的药物。慢性酒精滥用导致神经元 感觉运动、记忆、心理和认知功能的退化和功能缺陷。我们和 其他人已经证明氧化信号是酒精诱导损伤的中心机制， 神经和功能缺陷。修复积累的氧化自由基可以作为一个 预防酗酒者神经损伤进展的有效策略。因此，该提案将 研究一种新的假设，即脑损伤以及相关的神经炎症和神经变性 由酒精诱导的氧化损伤引起的损伤可以通过激活抗氧化信号Nrf 2来修复。 （核因子E2相关因子2）途径。Nrf 2转录系统是一种内源性防御系统， 增强许多解毒，细胞保护和抗炎基因表达的机制， 与其调控区中的抗氧化反应元件（ARE）相互作用。NRF 2有可能成为 减轻酒精诱导的神经损伤的新的治疗靶点。我们的核心假设是， 抗氧化剂促进转录因子Nrf 2的激活可抑制氧化应激诱导的 与过量饮酒有关的病理生理变化。这些变化包括激活 转化生长因子β1（TGF-β1）和基质金属蛋白酶（MMPs），神经炎症反应， 和神经退化Nrf 2转录因子的激活与内源性抗氧化剂的上调 将通过用Nrf 2激活剂III达特肽（Nrf 2肽）处理动物来实现酶的活性。我们将 将Nrf 2肽全身性（皮下）给予摄入酒精的小鼠，并评价其治疗效果。 在特定区域（如前额叶）减轻酒精相关神经损伤的潜力 皮质海马和小脑这项研究不仅验证了Nrf 2的因果关系， 肽在减轻AUD中的氧化应激中的作用，而且还鉴定了Nrf 2转录的机制调节 因子激活的抗氧化基因及其与Nrf 2的相互作用，通过ChIP-qPCR和ChIP-Seq.的 Nrf 2的保护作用将通过评估其对细胞基因表达和蛋白水平的影响来确定。 主要的抗氧化、炎症和凋亡蛋白。我们将验证Nrf 2肽在Nrf 2中的作用， 敲除（KO）小鼠（Nrf 2 −/−）。我们还将使用一组行为测试来评估认知， 与Nrf 2肽治疗相关的感觉-运动反馈和心理行为恢复 在野生型和Nrf 2-/-小鼠中暴露于酒精后。我们将比较结果与对照肽 （随机序列与达特）处理的动物。我们预计，这项研究的结果将 广泛的临床相关性。