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

神经退行性疾病，以进行性神经功能障碍和神经元为特征 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缓解而不是治愈的，迫切需要新的 减少或防止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，已被证明调节受 各种病理情况。尽管有这种已知的作用，但在受损神经元中受体是如何被激活的 它调节细胞死亡的机制也鲜为人知。利用培养的多巴胺能 细胞，我们最近发现了一种新的、不依赖于配体的机制，通过这种机制，p75NTR在 对氧化应激的反应。然而，与这种新的受体激活相关的信号事件 这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氏症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变性有关的疾病 中脑腹侧的黑质。考虑到这些因素，我们建议评估以下措施的效果 P75NTR在细胞培养和帕金森病动物模型中对多巴胺能神经变性的影响。目标I： 这一应用是为了研究氧化应激诱导p75NTR信号转导的机制。 生化分析将使用培养细胞的裂解物来确定各种p75NTR的作用。 氧化应激诱导的p75NTR信号转导中的相互作用。拟议工作的目标二是利用封锁 通过siRNA介导的基因敲除、基因缺失或药物抑制来评估p75NTR信号转导 受体在细胞培养和帕金森病小鼠模型多巴胺能神经变性中的作用 疾病。因为多巴胺能神经元轴突变性是先于 帕金森氏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、研究等方面的个人指导 方法、数据分析和调查结果的交流。通过支持这项有价值的研究，一个领域 格兰特将为学生提供有影响力的研究经验，并加强 EKU，一个加速重视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.