Role of androgens and activity in axon regeneration

描述(申请人提供)：每年有超过20万名患者因周围神经损伤而接受治疗。大约90%的患者无法恢复受伤肢体的完全运动。轴突再生缓慢和/或轴突靶向错误最常被归咎于这些功能不良的结果。周围神经损伤后，通过运动或电刺激等方式增加神经元活性，可促进轴突再生。我们已经证明，脑源性神经营养因子(BDNF)在轴突再生的神经元中的表达是这种增强所必需的，但男性和女性都需要通过雄激素受体发出信号。这些受体的配体雄激素的来源尚不清楚，特别是在女性身上。我们假设，它们的可用性可以通过神经元活动对类固醇转换酶的影响来改变。通过测量这些酶在神经元和非神经元细胞中对神经元活性增加的反应，我们预计我们可以确定促进轴突再生的雄激素来源。促进轴突再生所需的雄激素活性的靶点也鲜为人知。在雄激素受体基因以细胞类型特异性方式敲除的小鼠中，通过评估神经元活性增加对轴突再生的影响，我们将能够确定雄激素受体介导的促进轴突再生的细胞需求。在这项拟议的研究中，我们将使用最新可用的技术组合来调查这些角色。在临床上，雄激素疗法已经在使用。雄激素的产生和信号传递的知识是为周围神经再生量身定做这一潜在疗法所必需的，并可以应用于其他神经退行性疾病。

DESCRIPTION (provided by applicant): More than 200,000 patients are treated every year for peripheral nerve injury. Approximately 90% of patients never recover full movement of an injured limb. Slow axon regeneration and/or misdirected axon targeting are most often blamed for these poor functional outcomes. Increased neuronal activity, such as through exercise or electrical stimulation, enhances axon regeneration following peripheral nerve injury. We have shown that brain derived neurotrophic factor (BDNF) expression in the neurons whose axons are regenerating is required for this enhancement, but also that signaling through androgen receptors is required in both males and females. The source of the ligands for these receptors, androgens, is not known, especially in females. We hypothesize that their availability could be altered by the effects of neuronal activity on steroid converting enzymes. By measuring the expression of these enzymes in both neuronal and non-neuronal cells in response to increased neuronal activity, we anticipate that we can identify the sources of androgen that promote enhanced axon regeneration. The targets of androgenic activity required to promote axon regeneration also are poorly known. By evaluating the effects of increased neuronal activity on axon regeneration in mice in which the androgen receptor gene is knocked out in a cell-type specific manner, we will be able to identify the cellular requirements for androgen receptor-mediated enhancement of axon regeneration. In this proposed study, we will use a combination of newly available technologies to investigate these roles. Clinically, androgen therapy is already in use. Knowledge of androgen production and signaling is needed to tailor this potential therapy for peripheral nerve regeneration and could be applied to other neurodegenerative diseases.