PREVENTION OF DENDRITIC ATROPHY AFTER MOTONEURON INJURY

运动神经元损伤后树突萎缩的预防

• 批准号: 7071835
• 负责人: DALE R SENGELAUB
• 金额: $ 19.93万
• 依托单位: TRUSTEES OF INDIANA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7071835
• 关键词: atrophy; brain derived neurotrophic factor; degenerative motor system disease; dendrites; disease /disorder prevention /control; electrophysiology; hormone regulation /control mechanism; immunocytochemistry; in situ hybridization; laboratory rat; motor neurons; nerve injury; neuromuscular disorder chemotherapy; sensory receptors; testosterone

DESCRIPTION (provided by applicant): Neurodegenerative diseases or nerve injury can result in the loss of spinal motoneurons. However, remaining motoneurons after such insults show a variety of morphological and functional changes. As a consequence of both the loss of some motoneurons and the secondary changes in other, remaining motoneurons, functional restoration is poor, and the time course of recovery is protracted at best. The development of animal models, for example involving direct spinal cord damage or peripheral nerve injury, have begun to yield clues to both the mechanisms involved in motoneuron pathology and potential therapeutic approaches. Our work will concentrate on motoneuron dendrites, which are essential for the reception and integration of information. Dendrites in motoneurons atrophy after nerve injury or the death of neighboring motoneurons, and preventing that atrophy, or improving its recovery, in motoneurons that survive the initial insult will have a major impact on the restoration of spinal function. We have begun to develop two models in the adult rat spinal cord, utilizing induced motoneuron death or peripheral nerve cuts that will allow us to examine potential ways of preventing, or accelerating recovery from, dendritic atrophy in remaining motoneurons. In our first model, we found that the death of neighboring motoneurons causes the dendritic arbor of the remaining motoneurons to atrophy, but that manipulation of steroid hormones, specifically testosterone, can prevent or reverse that atrophy. Using morphological methods, we will determine if there is a dose/effect relationship for testosterone and dendritic protection, and if so, establish the minimum amount of testosterone required. We will also test the degree of functional recovery produced by these manipulations using electrophysiological methods. Using morphological methods, we will determine if there are critical temporal limits to the therapeutic window for protection from dendritic atrophy, and whether androgen prevents or accelerates recovery from dendritic atrophy. In our second model, we found an interactive effect of testosterone with brain-derived neurotrophic factor (BDNF) in preventing dendritic atrophy after cutting peripheral motor nerves. We will test whether the expression of BDNF in muscle or motoneurons, or its receptors, could be regulated by androgens, utilizing in situ hybridization and immunohistochemical techniques Together, results from studies using these two models will be informative about the therapeutic role for steroid hormones in treating spinal cord disease or nerve injury.

描述(申请人提供)：神经退行性疾病或神经损伤可导致脊髓运动神经元的丢失。然而，在这样的侮辱后，剩下的运动神经元表现出各种形态和功能的变化。由于一些运动神经元的丧失和其他剩余运动神经元的继发性改变，功能恢复很差，恢复的时间充其量是漫长的。动物模型的发展，例如涉及直接脊髓损伤或周围神经损伤，已经开始为运动神经元病理涉及的机制和潜在的治疗方法提供线索。我们的工作将集中在运动神经元树突上，这是信息接收和整合所必需的。在神经损伤或邻近运动神经元死亡后，运动神经元中的树突萎缩，而阻止这种萎缩，或改善其恢复，在最初的损伤中幸存下来的运动神经元将对脊髓功能的恢复产生重大影响。我们已经开始在成年大鼠脊髓中建立两种模型，利用诱导的运动神经元死亡或周围神经切断，这将使我们能够检查预防或加速剩余运动神经元树突状萎缩的潜在方法。在我们的第一个模型中，我们发现邻近运动神经元的死亡会导致剩余运动神经元的树突状树枝萎缩，但操纵类固醇激素，特别是睾丸素，可以防止或逆转这种萎缩。使用形态学方法，我们将确定睾丸激素和树突状细胞保护是否存在剂量/效应关系，如果是，则建立所需的最低睾丸素数量。我们还将使用电生理学方法测试这些手法所产生的功能恢复程度。使用形态学方法，我们将确定预防树突状萎缩的治疗窗口是否存在关键的时间限制，以及雄激素是否阻止或加速树突状萎缩的恢复。在我们的第二个模型中，我们发现睾酮和脑源性神经营养因子(BDNF)在预防周围运动神经切断后树突状细胞萎缩方面存在交互作用。我们将利用原位杂交和免疫组织化学技术，测试BDNF在肌肉或运动神经元或其受体中的表达是否可以受到雄激素的调节，使用这两种模型的研究结果将为类固醇激素在治疗脊髓疾病或神经损伤中的治疗作用提供信息。