The Norepinephrine transporter as a therapeutic target for treatment of alpha-synuclein pathology in PD

去甲肾上腺素转运蛋白作为治疗 PD α-突触核蛋白病理的治疗靶点

• 批准号: 10195789
• 负责人: Nikhil Urs
• 金额: $ 41.94万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10195789
• 关键词: APP-PS1; Alzheimer' s Disease; Anatomy; Anosmia; Antibodies; Autopsy; Behavioral; Biological Assay; Brain; Brain Diseases; Brain region; Cells; Cognitive; Consequentialism; Constipation; Corpus striatum structure; Data; Desipramine; Disease; Disease Progression; Dopamine; Dorsal; Economic Burden; FDA approved; Functional disorder; Genetic; Goals; Grant; High Pressure Liquid Chromatography; Histologic; Inflammation; Injections; Knock-out; Knockout Mice; Knowledge; Label; Lead; Lewy Bodies; Lewy body pathology; Lewy neurites; Light; Measures; Mediating; Medical; Microglia; Mission; Motor; Mus; National Institute of Neurological Disorders and Stroke; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Norepinephrine; Parkinson Disease; Pathogenesis; Pathogenicity; Pathologic; Pathology; Pharmacology; Pharmacotherapy; Physiological; Pilot Projects; Population; Prevalence; Research; Sensory; Structure; Substantia nigra structure; Testing; Therapeutic; Toxin; Transgenic Mice; aging population; alpha synuclein; beta amyloid pathology; cognitive disability; dopaminergic neuron; experimental study; functional disability; high risk; insight; motor behavior; motor deficit; nervous system disorder; neuroinflammation; neuron loss; non-motor symptom; noradrenaline transporter; olfactory bulb; parent grant; pars compacta; synucleinopathy; therapeutic target; tool

The Norepinephrine transporter as a therapeutic target for treatment of alpha-synuclein pathology in PD Parkinson’s disease (PD) is a neurodegenerative disorder prevalent in ~1% of the population, making it a medically important problem, especially in the aging population. The economic burden for PD exceeds $10 Billion annually in the US and the prevalence of PD is projected to significantly increase in the coming decades. PD is characterized by severe motor deficits as well as non- motor symptoms such as loss of smell, constipation and cognitive disability. Sporadic PD is characterized by widespread alpha-synuclein (α-syn) positive inclusions called Lewy bodies and neurites in the brain, along with loss of dopamine neurons of the substantia nigra pars compacta (SNpc). However, the underlying mechanisms of α-syn mediated pathogenesis, progression, and neurodegeneration are still not clear. Consequentially, strategies for treating pathogenesis and progression of sporadic PD have not been well developed. Previous studies and our preliminary data suggest that the norepinephrine transporter (NET) is a potential therapeutic target for α-syn pathology in PD. Our overall hypothesis is that genetic deletion or pharmacological inhibition of NET will reduce α-Syn propagation, neurodegeneration, neuroinflammation and behavioral deficits. We will test our hypothesis through two aims. In aim1, we will test the effect of NET deletion or inhibition on histological markers of α-syn aggregation and propagation, dopamine neurodegeneration and neuroinflammation. In aim2, we will test the effect of NET deletion or inhibition on motor deficits. The proposed experiments will not only provide an insight into the underlying mechanism of α- syn propagation and vulnerability, but more importantly reveal a potential therapeutic strategy for ameliorating functional impairments and slow progression of PD pathology.

去甲肾上腺素转运蛋白作为治疗α-突触核蛋白的治疗靶点 PD病理学 帕金森病（PD）是一种神经退行性疾病，约占人口的1%， 使其成为医学上的重要问题，特别是在老龄化人口中。经济负担 在美国，PD每年的治疗费用超过100亿美元， 在未来几十年中，增长。PD的特征是严重的运动缺陷以及非运动缺陷。 运动症状，如嗅觉丧失、便秘和认知障碍。散发性PD是 特征为广泛分布的α-突触核蛋白（α-syn）阳性内含物，称为路易体， 脑中的神经突，沿着黑质腹侧部多巴胺神经元的丢失 （SNpc）。然而，α-syn介导的发病机制，进展， 神经退行性变仍不清楚。因此，治疗发病机制和 散发性PD进展尚未得到很好的研究。先前的研究和我们的初步研究 数据表明，去甲肾上腺素转运蛋白（NET）是α-syn的潜在治疗靶点， 病理学我们的总体假设是，基因缺失或药物抑制 NET将减少α-Syn的传播，神经变性，神经炎症和行为 赤字我们将通过两个目标来检验我们的假设。在aim 1中，我们将测试NET的效果 α-syn聚集和增殖、多巴胺的组织学标志物缺失或抑制 神经变性和神经炎症。在aim 2中，我们将测试NET删除或 抑制运动缺陷。 所提出的实验不仅将提供对α- 同步传播和脆弱性，但更重要的是揭示了一个潜在的治疗策略， 改善功能损伤和减缓PD病理学的进展。