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: 9025810
• 负责人: Patricia J Ward
• 金额: $ 5.8万
• 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/9025810
• 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; Health; Individual; Intervention; Knock-out; Knockout Mice; Knowledge; Ligands; Light; Limb structure; LoxP-flanked allele; Measures; Mediating; Medical; Messenger RNA; Microglia; Motor; Motor Neurons; Movement; Mus; Muscle; Natural regeneration; Nerve; Neurodegenerative Disorders; Neuroglia; Neurons; Oligodendroglia; Operative Surgical Procedures; Optics; Outcome Measure; Patients; 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; androgenic; axon regeneration; base; cell type; functional outcomes; injured; innovation; male; men; nerve injury; nerve transection; novel; optogenetics; peripheral nerve regeneration; peripheral nerve transection; promoter; receptor; recombinase-mediated cassette exchange; 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名患者接受周围神经损伤治疗。大约90%的患者无法完全恢复受伤肢体的运动。缓慢的轴突再生和/或错误的轴突靶向通常被归咎于这些不良的功能结果。增加的神经元活动，例如通过运动或电刺激，增强周围神经损伤后的轴突再生。我们已经表明，脑源性神经营养因子（BDNF）的神经元的轴突再生的表达是需要这种增强，但也需要通过雄激素受体的信号在男性和女性。这些受体的配体（雄激素）的来源尚不清楚，尤其是在女性中。我们推测，它们的可用性可以通过神经元活动对类固醇转化酶的影响而改变。通过测量这些酶在神经元和非神经元细胞中的表达，以响应增加的神经元活性，我们预计，我们可以确定雄激素的来源，促进增强轴突再生。促进轴突再生所需的雄激素活性的靶点也知之甚少。通过评估增加神经元活性对雄激素受体基因以细胞类型特异性方式敲除的小鼠轴突再生的影响，我们将能够确定雄激素受体介导的轴突再生增强的细胞要求。在这项拟议的研究中，我们将使用新的可用技术的组合来调查这些角色。临床上，雄激素治疗已经在使用。雄激素的产生和信号传导的知识是必要的，以定制这种潜在的治疗周围神经再生，并可应用于其他神经退行性疾病。

项目成果

HIF1a and angiogenesis are critical for the regenerative effects of exercise.

HIF1a 和血管生成对于运动的再生作用至关重要。

• 发表时间: 2022
• 期刊: FASEB journal : official publication of the Federation of American Societies for Experimental Biology
• 作者: Ward,Patricia;Wariyar,Supriya;Tian,Tina;Pottorf,Tana;Brown,Alden
• 通讯作者: Brown,Alden