Targeting spermine oxidase to prevent vision loss in Multiple Sclerosis

靶向精胺氧化酶预防多发性硬化症患者的视力丧失

• 批准号: 10257895
• 负责人: Priya Narayanan
• 金额: --
• 依托单位: CHARLIE NORWOOD VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-10-01 至 2025-09-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10257895
• 关键词: Acrolein; Affect; Aldehydes; Antioxidants; Axon; Behavioral; Blindness; Blood-Retinal Barrier; Brain; Clinical; Cognitive; Contrast Sensitivity; Defect; Demyelinations; Dependovirus; Development; Disease; Disease Progression; Down-Regulation; Enzymes; Experimental Autoimmune Encephalomyelitis; Experimental Models; Eye; Functional disorder; Gliosis; Goals; Health; Inflammation; Inflammatory; Inflammatory Response; Lead; Measures; Mediating; Mediator of activation protein; Metabolic Pathway; Mission; Modeling; Modification; Molecular; Morphology; Motor; Multiple Sclerosis; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neuronal Dysfunction; Neurons; New Agents; Onset of illness; Optic Nerve; Optic Neuritis; Outcome; Oxidative Stress; Parkinson Disease; Pathology; Pharmaceutical Preparations; Pharmacology; Phase; Play; Polyamines; Proteins; Quality of life; Research; Research Personnel; Retina; Retinal Ganglion Cells; Role; Sampling; Spinal cord injury; Structure; Symptoms; Testing; Therapeutic; Thinness; Transgenic Mice; Traumatic Brain Injury; Unmyelinated Nerve Fibers; Up-Regulation; Veterans; Vision; Visual Acuity; Visual Pathways; Visual impairment; adduct; behavioral outcome; clinically significant; disability; disabling disease; genetic approach; improved; inhibitor; insight; mitochondrial dysfunction; motor deficit; motor impairment; multiple sclerosis patient; multiple sclerosis treatment; nervous system disorder; neuroinflammation; neuronal survival; new therapeutic target; novel; novel therapeutic intervention; overexpression; oxidation; oxidative damage; polyamine oxidase; pre-clinical; preservation; prevent; progressive neurodegeneration; response; retinal nerve fiber layer; retinal neuron; small hairpin RNA; targeted agent; targeted treatment; theories; therapeutic target; tool; translational approach; treatment effect; visual dysfunction; visual motor

PROJECT SUMMARY Multiple sclerosis (MS) is a highly disabling neurological disease affecting veterans, characterized by demyelination, inflammatory responses and neurodegeneration. Current medications available for treating MS are only partially effective as they specifically target the inflammatory phase, but not the neurodegenerative phase, and therefore have limited effects on long-term disability. Increasing evidences suggest that neurodegeneration plays a crucial role in the MS pathology. However, the mechanisms underlying the progressive neurodegeneration are poorly studied in MS. Hence, there is a great need for identifying new agents that target the neurodegenerative stage of the disease. Our goal is to contribute to the treatment of MS, by defining the specific role of Spermine Oxidase (SMOX, an important enzyme in polyamine metabolic pathway), in mediating neurodegeneration in the MS retina and by demonstrating its potential as a therapeutic target for MS treatment. Our central hypothesis is that SMOX is upregulated in retinal neurons, resulting in increased polyamine oxidation and release of acrolein in the MS retina. Our hypothesis predicts that formation of various protein-acrolein adducts causes oxidative damage in the retina, leading to neuronal dysfunction. Our objectives are: 1) characterize molecular mechanisms involved in SMOX-induced neuronal damage in the experimental model for MS; 2) determine the impact of SMOX overexpression/downregulation in mediating neurodegeneration in the experimental model of MS; and 3) determine the therapeutic potential of inhibiting SMOX for the treatment of MS. Our expected outcomes include 1) identification of SMOX induced molecular changes by which neuronal damage occurs in MS; 2) demonstration of alterations in retinal neuronal survival and function in response to manipulation of SMOX expression in the experimental model; and 3) preservation of visual acuity, contrast sensitivity, retinal structure and reduced inflammation in response to SMOX blockade. Our studies will impact the field of MS by providing new and significant information on mechanisms by which neurodegeneration occurs in MS, and thus can lead to the development of accurate and efficacious targeted therapies to improve the quality of life in veterans affected by the disease. Results coming out these studies may provide translational strategies for MS disease progression and can also be applicable to cognitive, behavioral and motor deficits in MS patients. Retina is known as “window to the brain” and hence targeting SMOX function has the potential to be evaluated as therapy for MS in general and is also applicable to other disabling diseases affecting veterans such as Traumatic brain injury, Parkinson’s disease and spinal cord injury.

项目摘要 多发性硬化症（MS）是一种高度致残的神经系统疾病，影响退伍军人，其特征是 脱髓鞘，炎症反应和神经变性。当前可用于治疗MS的药物 仅是部分有效的，因为它们专门针对炎症阶段，而不是神经退行性阶段 阶段，因此对长期残疾的影响有限。越来越多的证据表明 神经变性在MS病理学中起着至关重要的作用。但是， 在MS中，进行性神经变性的研究很差。因此，肯定要识别新代理商 该靶向该疾病的神经退行性阶段。我们的目标是通过 定义精子氧化酶（SMOX，多胺代谢途径中的重要酶）的特定作用， 在MS Retina中介导神经退行性的过程中，并通过证明其作为治疗靶点的潜力 MS治疗。我们的中心假设是SMOX在残留神经元中上调，导致增加 多胺氧化和MS视网膜中丙烯醛的释放。我们的假设预测各种形成 蛋白质 - 丙酸加合物在视网膜中引起氧化损伤，导致神经元功能障碍。我们的目标 是：1）表征实验中参与SMOX诱导的神经元损伤的分子机制 MS的模型； 2）确定SMOX过表达/下调在介导神经变性中的影响 在MS的实验模型中； 3）确定抑制SMOX治疗的治疗潜力 MS。我们的预期结果包括1）鉴定SMOX诱导的分子变化 神经元损害发生在MS中； 2）证明残留神经元存活和功能的改变 对实验模型中SMOX表达操纵的响应； 3）视力保存， 对比敏感性，残留结构和减少注射，以响应SMOX封锁。我们的研究将 通过提供有关神经变性的机制的新的和重要信息，影响MS的领域 发生在MS中，因此可能导致精确有效的靶向疗法的发展以改善 受该疾病影响的退伍军人生活质量。这些研究的结果可能会提供翻译 MS疾病进展的策略，也可以适用于认知，行为和运动的定义 MS患者。视网膜被称为“大脑窗口”，因此靶向SMOX功能有可能 通常作为MS的治疗评估，也适用于其他影响退伍军人的残疾疾病 例如脑损伤，帕金森氏病和脊髓损伤。