GROWTH FACTORS IN THE ADULT AND AGING BRAIN

成人和衰老大脑中的生长因子

• 批准号: 2909628
• 负责人: MARIANN M BLUM
• 金额: $ 23万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-05-01 至 2000-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2909628
• 关键词: Parkinson's disease; age difference; aging; disease /disorder model; dopamine; gene expression; genetic strain; hormone regulation /control mechanism; laboratory mouse; limbic system; methylphenyltetrahydropyridine; nervous system regeneration; neural degeneration; neural plasticity; neurotoxins; neurotrophic factors; substantia nigra; thyroid hormones; tissue /cell culture; transforming growth factors

Parkinson's disease is characterized by the premature neurodegeneration of nigrostriatal dopamine neurons. In order to discover what may be causing this cellular loss or provide a treatment that may decrease the progression of the disease, studies in our laboratory have been focused on identifying factors that are important for the survival and plasticity of dopamine neurons. In order to carry out this goal, we have been utilizing three mouse models. The first, is the weaver mutant mouse in which abnormal development of the dopaminergic nigrostriatal fibers is first observed followed by degeneration of dopaminergic neurons in a similar pattern to what is found in Parkinson's disease, TGF-alpha, during the time of dopaminergic neuronal degeneration. In addition, we have found that these mice also have decreased levels of thyroid hormone, a potent regulator of brain development. Therefore, we have proposed studies aimed at discovering whether the decreases in either TGF-alpha or thyroid hormone are responsible for the neurodegeneration of dopamine neurons in the weaver mutant mouse. Recently, another mutant mouse has been discovered, waved-1, which has a deficiency in TGF-alpha expression. The availability of this second mouse mutant, allows us to specifically test whether a deficiency in TGF-alpha alone results in the degeneration of dopamine neurons or increase their sensitivity to the neurotoxin, 1- methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). There is evidence that the more resilient mesolimbic dopaminergic neurons are able to undergo collateral axonal sprouting in response to degeneration of the nigrostrital neurons. Thus, these dopaminergic neurons represent a potential target to stimulate collateral axonal sprouting after neurodegeneration of dopamine neurons in the substantia nigra. However, there is an age-related loss in the capacity of these neurons to spontaneously sprout. Therefore, in the last mouse model system we investigate what endogenous factors may be responsible for lesion-induced plasticity of dopamine neurons in young animals, how their induction in response to injury is regulated, and whether lesion-induced activation becomes the limiting factor in the age-related loss of dopaminergic plasticity. The results of these studies may reveal therapeutic possibilities for enhancing the recovery of dopamine neurons in neurodegenerative diseases in which spontaneous recovery does not normally occur.

帕金森病的特征是过早的神经变性 黑质纹状体多巴胺神经元。 为了找出可能的原因 这种细胞损失或提供可能减少细胞损失的治疗 疾病的进展，我们实验室的研究重点是 确定对生存和可塑性重要的因素 多巴胺神经元。 为了实现这一目标，我们一直在利用 三种鼠标型号。 第一个是织布突变小鼠，其中 首先是多巴胺能黑质纹状体纤维的异常发育 观察到多巴胺能神经元在类似的情况下发生退化 与帕金森病中发现的 TGF-α 模式相似 多巴胺能神经元变性的时间。 此外，我们还发现 这些小鼠的甲状腺激素水平也降低了，甲状腺激素是一种有效的 大脑发育的调节者。 因此，我们提出研究目标 发现 TGF-α 或甲状腺水平是否下降 激素是导致多巴胺神经元神经变性的原因 织布突变小鼠。 最近，另一只突变小鼠被 发现了waved-1，其TGF-α表达存在缺陷。 这 第二种小鼠突变体的可用性使我们能够专门测试 TGF-α 单独缺乏是否会导致 多巴胺神经元或增加其对神经毒素的敏感性，1- 甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）。 有证据表明 更有弹性的中边缘多巴胺能神经元能够经历 侧枝轴突发芽响应退化 黑质纹状体神经元。 因此，这些多巴胺能神经元代表 刺激侧支轴突萌芽的潜在目标 黑质多巴胺神经元的神经变性。 然而， 这些神经元的能力会随着年龄的增长而丧失 自发发芽。 因此，在最后一个小鼠模型系统中，我们 研究哪些内源性因素可能导致病变诱发 幼年动物多巴胺神经元的可塑性，它们是如何诱导的 对损伤的反应受到调节，以及损伤是否诱导激活 成为与年龄相关的多巴胺能丧失的限制因素 可塑性。 这些研究的结果可能揭示治疗方法 增强多巴胺神经元恢复的可能性 神经退行性疾病，通常无法自行恢复 发生。