TRH IN MOTOR NEURON DISEASE

这项拟议的研究的目标是发现促甲状腺激素是如何释放的。 激素(TRH，pGLU-His-Pro-NH2)在 运动神经元疾病，特别是肌萎缩侧索硬化症(ALS)。二 将使用运动神经元疾病的动物模型，一个是病毒模型，一个是病毒模型 遗传性，两种都在老鼠身上。第一种是感染逆转录病毒(小鼠 白血病病毒，MuLV)导致后肢瘫痪一段时间 疗程视剂量而定，第二种(主要用于确认 病毒模型中的结果)是Wobbler(WR)突变体，是常染色体 导致变异性进行性前肢瘫痪的隐性疾病 从几个星期大的时候开始。脊椎的生化测量 受影响的小鼠的脐带将尽可能集中在TRH的受体上 涉及运动神经元病的病理生理学的站点。他们 代表将TRH的存在转化为响应的第一步 并通过绑定测量容易地检测到。以前的工作有 开发了一种改进的配体(H3)(3-Me-His2)TRH([H]3MeTRH)来研究这种 受体，并使用它和(H3)TRH，已经确定了它们的存在和 在脊髓和中枢神经系统的其他区域的身份， 物种在密度、定位等方面存在差异 通过解剖和放射自显影在兔脊髓中观察到 在含有TRH的神经末梢被破坏后， 以及P物质和某些物质对它们在试管中的调节作用 苯二氮卓类。其他测量将包括TRH水平(通过 放射免疫分析)和各种胆碱能标志物(胆碱 乙酰转移酶等。)作为运动神经元存活的指标。结果： 生化测量将与电生理相关 受感染小鼠脊髓标本的测定， 寻找伴随生化反应的TRH反应的变化 改变。进一步的实验将检查生化标志物的变化。 正常和MuLV感染小鼠脊髓对TRH的反应 5，7-二羟色胺治疗(破坏含有 5-羟色胺和共定位的TRH)，观察TRH耗竭是否会加速 运动神经元病的进展以及TRH和TRH治疗的效果 其类似物对两种运动神经元模型小鼠运动诱发电位的影响 疾病。

The goal of the proposed research is to discover how thyrotropin-releasing hormone (TRH,pGLU-His-Pro-NH2) produces therapeutically-useful effects in motor neuron disease, notably amyotrophic lateral sclerosis (ALS). Two animal models of motor neuron disease will be used, one viral and one hereditary, both in mice. The first is infection with a retrovirus (murine leukemia virus, MuLV) leading to paralysis in the hind limbs with a time course depending on dose and the second (primarily for confirmation of results in the virus model) is the wobbler (wr) mutant, an autosomal recessive condition leading to variable and progressive forelimb paralysis starting at several weeks of age. Biochemical measurements in the spinal cords of affected mice will concentrate on receptors for TRH as a possible site involved in the pathophysiology of motor neuron disease. They represent the first step in translating the presence of TRH into a response and are readily detected by binding measurements. Previous work has developed an improved ligand,(H3)(3-Me-His2)TRH([H]3MeTRH), to study such receptors and, using it and (H3)TRH, has established their presence and identity in the spinal cord and other areas of the central nervous system, the existence of species differences in their density, their localization in rabbit spinal cord by dissection and autoradiography, their "up-regulation" following destruction of TRH-containing nerve terminals, and their modulation in the test tube by substance P and certain benzodiazepines. Other measurements will include levels of TRH (by radioimmunoassay) and various cholinergic markers (choline acetyltransferase, etc.) as indices of motor neuron survival. Results of biochemical measurements will be correlated with electrophysiological measurements on the isolated spinal cord preparation from affected mice, looking for changes in responses to TRH which accompany biochemical changes. Further experiments will examine changes in biochemical markers and responses to TRH in spinal cords of normal and MuLV-infected mice after treatment with 5,7-dihydroxytryptamine (destroys neurons containing serotonin and colocalized TRH), seeing if TRH depletion speeds the progression of motor neuron disease, and effects of treatment with TRH and its analogs on motr performance in the two murine models of motor neuron disease.