The Role of the p75 Neurotrophin Receptor in Dopaminergic Neurodegeneration Induced by Oxidative Stress.

p75 神经营养素受体在氧化应激诱导的多巴胺能神经变性中的作用。

• 批准号: 10437963
• 负责人: BRADLEY R KRAEMER
• 金额: $ 43.8万
• 依托单位: UNIVERSITY OF ALABAMA IN HUNTSVILLE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-15 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10437963
• 关键词: Address; Adverse effects; Affect; Alzheimer' s disease model; Animal Model; Binding; Biochemical; Biological Assay; Biomedical Research; Blocking Antibodies; Brain region; Cell Culture Techniques; Cell Death; Cell Nucleus; Cells; Communication; Corpus striatum structure; Cultured Cells; Data Analyses; Disease; Dopaminergic Cell; Economic Burden; Elderly; Environment; Etiology; Event; Experimental Designs; Fluorescence; Genetic; Grant; In Situ Nick-End Labeling; Individual; Institution; Integral Membrane Protein; Investigation; Kentucky; Knockout Mice; Label; Laboratories; Lateral; Lead; Ligand Binding; Ligands; MAPK8 gene; Measures; Mediating; Mentorship; Methods; Midbrain structure; Modeling; Molecular; Morbidity - disease rate; NGFR Protein; Nerve Degeneration; Neuraxis; Neurites; Neurodegenerative Disorders; Neuronal Dysfunction; Neurons; Neurotoxins; Oxidative Stress; Oxidopamine; Parkinson Disease; Pathologic; Pharmacology; Physiological; Population; Production; Proteins; Proteolysis; Reactive Oxygen Species; Receptor Activation; Research; Research Methodology; Research Project Grants; Role; Rotenone; Science; Signal Transduction; Small Interfering RNA; Spinal Cord; Stains; Students; Substantia nigra structure; Tissue Sample; Tissues; Tyrosine 3-Monooxygenase; Universities; Western Blotting; Wild Type Mouse; Work; axonal degeneration; design; dopamine transporter; dopaminergic neuron; experience; experimental study; immunoreactivity; improved; in vivo; inhibitor; knock-down; literacy; meetings; mortality; mouse model; nerve supply; neuron loss; neurotrophic factor; novel; palliative; pars compacta; prevent; progressive neurodegeneration; receptor; response; treatment strategy; undergraduate student

Neurodegenerative diseases, which are characterized by progressive neural dysfunction and neuronal death, are a common cause of morbidity and mortality in the elderly. Because current treatment strategies for most neurodegenerative disorders are palliative rather than curative, there is an urgent need for novel treatment strategies that reduce or prevent progressive neurodegeneration. The p75 neurotrophin receptor (p75NTR) is a transmembrane protein that has been demonstrated to regulate the death of neurons affected by a variety of pathological conditions. Despite this known role, how the receptor is activated in damaged neurons and the mechanisms through which it regulates cell death are poorly understood. Using cultured dopaminergic cells, we recently discovered a novel, ligand-independent mechanism through which p75NTR is activated in response to oxidative stress. However, the signaling events associated with this new receptor activation mechanism and the physiological consequences of such events remain incompletely understood. Investigations in this regard may be particularly important to understanding the progression of Parkinson’s disease, a disorder associated with oxidative stress and progressive degeneration of dopaminergic neurons in the substantia nigra of the ventral midbrain. With these considerations, we propose to evaluate the effects of p75NTR on dopaminergic neurodegeneration in cell culture and animal models of Parkinson’s disease. Aim I of this application is to characterize the mechanisms through which oxidative stress induces p75NTR signaling. Biochemical assays will be performed using lysates of cultured cells to identify the roles of various p75NTR interactors in oxidative stress-induced p75NTR signaling. Aim II of the proposed work is to use blockade of p75NTR signaling by siRNA-mediated knockdown, genetic deletion, or pharmacological inhibition to evaluate the effects of the receptor on dopaminergic neurodegeneration in cell culture or mouse models of Parkinson’s disease. Since axonal degeneration in dopaminergic neurons is a key, early-stage event that precedes neuronal death in individuals with Parkinson’s disease, Aim III of the proposed research project is to evaluate the effects of p75NTR signaling on axonal degeneration induced by oxidative stress. All studies in this proposal will involve undergraduate students at Eastern Kentucky University (EKU). These students will also participate in weekly lab meetings and receive personal mentorship in science literacy, experimental design, research methodology, data analysis, and communication of findings. By supporting this meritorious research, an AREA grant would provide impactful research experiences for students and strengthen the scientific environment at EKU, an institution with accelerating emphasis on biomedical research.

神经退行性疾病，其特征是进行性神经功能障碍和神经元 死亡，是老年人发病和死亡的常见原因。因为目前的治疗策略 大多数神经退行性疾病都是姑息性而非治愈性的，因此迫切需要新的治疗方法 减少或预防进行性神经变性的治疗策略。 p75 神经营养素受体 (p75NTR) 是一种跨膜蛋白，已被证明可以调节受 各种病理状况。尽管有这种已知的作用，但受体如何在受损的神经元中被激活 人们对它调节细胞死亡的机制知之甚少。使用培养的多巴胺能 细胞中，我们最近发现了一种新颖的、不依赖于配体的机制，通过该机制 p75NTR 在 对氧化应激的反应。然而，与这种新受体激活相关的信号事件 此类事件的机制和生理后果仍不完全清楚。 这方面的研究对于了解帕金森病的进展可能特别重要 疾病，一种与氧化应激和多巴胺能神经元进行性退化相关的疾病 中脑腹侧的黑质。考虑到这些因素，我们建议评估 p75NTR 对帕金森病细胞培养和动物模型中多巴胺能神经变性的影响。我的目标是 该应用旨在表征氧化应激诱导 p75NTR 信号传导的机制。 将使用培养细胞的裂解物进行生化测定，以确定各种 p75NTR 的作用 氧化应激诱导的 p75NTR 信号传导中的相互作用因子。拟议工作的目标二是利用封锁 通过 siRNA 介导的敲低、基因缺失或药理抑制来评估 p75NTR 信号转导 受体对帕金森病细胞培养物或小鼠模型中多巴胺能神经变性的影响 疾病。由于多巴胺能神经元的轴突变性是一个关键的早期事件，发生在 帕金森病患者的神经元死亡，拟议研究项目的目标 III 是评估 p75NTR 信号对氧化应激诱导的轴突变性的影响。本提案中的所有研究 将涉及东肯塔基大学 (EKU) 的本科生。这些学生也将参加 参加每周的实验室会议，并接受科学素养、实验设计、研究方面的个人指导 方法、数据分析和结果交流。通过支持这项有价值的研究，AREA 赠款将为学生提供有影响力的研究经验，并加强大学的科学环境 EKU，一个日益重视生物医学研究的机构。