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

神经退行性疾病，其特征在于进行性神经功能障碍和神经元损伤。 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是姑息性的而不是治愈性的，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神经营养因子受体 （p75NTR）是一种跨膜蛋白，其已被证明调节受以下影响的神经元的死亡： 各种病理状况。尽管这种已知的作用，受体是如何在受损的神经元中被激活的， 而它调节细胞死亡的机制也知之甚少。利用培养的多巴胺能神经 细胞，我们最近发现了一种新的，配体非依赖性的机制，通过这种机制，p75NTR被激活， 氧化应激反应。然而，与这种新受体激活相关的信号事件 这些事件的机制和生理后果仍然不完全清楚。 在这方面的调查可能是特别重要的了解帕金森氏症的进展 疾病，一种与多巴胺能神经元的氧化应激和进行性变性相关的疾病， 中脑腹侧的黑质基于这些考虑，我们建议评估 p75 NTR对细胞培养和帕金森病动物模型中多巴胺能神经变性的影响目标I 本申请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物化学测定以鉴定各种p75 NTR的作用。 氧化应激诱导的p75NTR信号传导中的相互作用。拟议工作的目的二是利用封锁 通过siRNA介导的敲低、遗传缺失或药理学抑制来评估p75NTR信号传导， 受体对细胞培养或帕金森病小鼠模型中多巴胺能神经变性的作用 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， 帕金森病患者的神经元死亡，拟议研究项目的目的III是评估 p75NTR信号通路在氧化应激诱导的轴突变性中的作用。本提案中的所有研究 将涉及东肯塔基州大学（EKU）的本科生。这些学生也将参加 在每周的实验室会议上，接受科学素养、实验设计、研究 方法、数据分析和结果交流。通过支持这项有价值的研究，一个地区 赠款将为学生提供有影响力的研究经验，并加强科学环境， EKU，一个加速强调生物医学研究的机构。

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.