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

基本信息

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
项目类别：
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&apos 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

项目摘要

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.

抽象的酒精是美国最常用和滥用的药物。慢性酒精滥用导致神经元感觉运动，记忆，心理和认知功能中的退化和功能缺陷。我们和其他人已经证明氧化信号传导是酒精诱导的损伤中的中心机制神经和功能性缺陷。累积氧化物自由基的补救可以用作防止酗酒者神经系统损害进展的有效策略。那，这个建议将研究一个新的假设，即脑损伤和相关的神经炎症和神经退行性通过激活抗氧化剂信号NRF2，可以修复由酒精引起的氧化损伤引起的（核因子E2相关因子2）途径。 NRF2转录系统是内源防御促进许多解毒，细胞保护和抗炎基因表达的机制与其调节区域中的抗氧化反应元件（IS）相互作用。 NRF2有可能成为一种新颖的治疗靶标，可减轻酒精引起的神经损害。我们的中心假设是抗氧化剂促进转录因子NRF2的激活减轻了氧化应激诱导的与摄入过多的酒精相关的病理生理变化。这些更改包括激活转化生长因子β1（TGF-β1）和基质金属蛋白酶（MMP），神经炎症反应，和神经变性。 NRF2转录因子的激活和内源性抗氧化剂的上调酶将通过用NRF2激活剂III TAT肽（NRF2肽）处理动物来实现酶。我们将在系统地（皮下）给饮酒摄入的小鼠摄取NRF2并评估其疗法减轻诸如前额叶等定义区域中与酒精相关的神经系统损害的潜力皮质，海马和小脑。拟议的研究不仅验证了NRF2的因果肽在缓解AUD中的氧化应激中因子激活的抗氧化剂基因及其与ChIP-QPCR和CHIP-SEQ与NRF2的相互作用。这 NRF2的保护作用将通过评估其对基因表达的影响和蛋白质水平来确定主要的抗氧化剂，炎症和凋亡蛋白。我们将验证NRF2中的NRF2的效果敲除（KO）小鼠（NRF2 - / - ）。我们还将使用一系列行为测试来评估认知，感觉运动反馈和与NRF2胡椒治疗相关的心理行为恢复野生型和NRF2 - / - 小鼠的酒精暴露后。我们将将结果与控制辣椒进行比较（用TAT随机序列）经过处理的动物。我们预计这项研究的发现将有广泛的临床相关性。