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: 10513305
• 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/10513305
• 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; Measures; Mediating; Mediator; 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; 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; pharmacologic; 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

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.

项目概要 多发性硬化症（MS）是一种影响退伍军人的高度致残的神经系统疾病，其特征是 目前可用于治疗多发性硬化症的药物包括脱髓鞘、炎症反应和神经变性。 仅部分有效，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。 然而，神经变性在 MS 病理学中起着至关重要的作用。 进行性神经变性在多发性硬化症中的研究很少，因此，非常需要鉴定新的药物。 针对该疾病的神经退行性阶段，我们的目标是通过以下方式为多发性硬化症的治疗做出贡献。 定义精胺氧化酶（SMOX，多胺代谢途径中的重要酶）的具体作用， 介导多发性硬化症视网膜神经变性，并证明其作为治疗靶点的潜力 MS 治疗的中心假设是 SMOX 在视网膜神经元中上调，导致视网膜神经元中的 SMOX 增加。 我们的假设预测，MS 视网膜中的多胺氧化和丙烯醛释放。 蛋白质-丙烯醛加合物会导致视网膜氧化损伤，导致神经元功能障碍。 是：1）表征实验中 SMOX 诱导的神经损伤涉及的分子机制 MS 模型；2) 确定 SMOX 过度表达/下调对介导神经变性的影响 在 MS 实验模型中；以及 3) 确定抑制 SMOX 的治疗潜力 我们的预期结果包括 1) 识别 SMOX 诱导的分子变化，通过这些变化 MS 中发生神经元损伤；2) 证明视网膜神经元存活和功能发生改变 实验模型中对 SMOX 表达操纵的反应；3) 视力的保持， 我们的研究将改善对比敏感度、视网膜结构和减少炎症反应。 通过提供有关神经退行性变机制的新的重要信息来影响多发性硬化症领域 发生在多发性硬化症中，因此可以开发出准确有效的靶向疗法来改善 这些研究的结果可能会提供转化。 多发性硬化症疾病进展的策略，也可适用于认知、行为和运动缺陷 多发性硬化症患者的视网膜被称为“大脑的窗口”，因此针对 SMOX 功能有可能 被评估为一般多发性硬化症的治疗方法，也适用于影响退伍军人的其他致残疾病 例如创伤性脑损伤、帕金森病和脊髓损伤。