Role of androgens and activity in axon regeneration

雄激素和活性在轴突再生中的作用

• 批准号: 8718645
• 负责人: Patricia J Ward
• 金额: $ 5.15万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-01 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8718645
• 关键词: Accounting; Afferent Neurons; Aging; Androgen Receptor; Androgen Therapy; Androgens; Astrocytes; Axon; Basic Science; Brain-Derived Neurotrophic Factor; Cations; Cell Separation; Cells; Centrifugation; Child; Electric Stimulation; Enzymes; Exercise; Female; Genetic; Individual; Intervention; Knock-out; Knockout Mice; Knowledge; Ligands; Light; Limb structure; Measures; Mediating; Medical; Messenger RNA; Microglia; Motor; Motor Neurons; Movement; Mus; Muscle; Natural regeneration; Nerve; Nerve Regeneration; Neurodegenerative Disorders; Neuroglia; Neurons; Oligodendroglia; Operative Surgical Procedures; Optics; Outcome Measure; Patients; Peripheral Nerves; Peripheral nerve injury; Physical therapy; Play; Population; Population Heterogeneity; Production; Proteins; Radioimmunoassay; Receptor Gene; Reporter; Research; Rhodopsin; Role; Sensory; Signal Transduction; Site; Source; Speed; Steroids; Surgical sutures; Technology; Woman; Work; axon regeneration; base; cell type; functional outcomes; injured; innovation; male; men; nerve injury; novel; optogenetics; promoter; public health relevance; receptor; reinnervation; research study; response; sciatic nerve

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.

描述（由申请人提供）：每年有超过 200,000 名周围神经损伤患者接受治疗。大约 90% 的患者永远无法恢复受伤肢体的完全运动。这些不良的功能结果最常被归咎于轴突再生缓慢和/或轴突靶向错误。神经元活动的增加（例如通过运动或电刺激）可增强周围神经损伤后的轴突再生。我们已经证明，轴突再生的神经元中脑源性神经营养因子（BDNF）的表达是这种增强所必需的，而且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，尤其是在女性中。我们假设神经元活动对类固醇转化酶的影响可能会改变它们的可用性。通过测量神经元和非神经元细胞中这些酶对神经元活动增加的反应的表达，我们预计我们可以确定促进轴突再生增强的雄激素来源。促进轴突再生所需的雄激素活性的目标也知之甚少。通过评估以细胞类型特异性方式敲除雄激素受体基因的小鼠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轴突再生增强的细胞需求。在这项拟议的研究中，我们将结合使用新可用的技术来研究这些角色。临床上，雄激素疗法已经投入使用。需要了解雄激素产生和信号传导的知识来定制这种针对周围神经再生的潜在疗法，并可应用于其他神经退行性疾病。