GROWTH FACTORS IN THE ADULT AND AGING BRAIN

成人和衰老大脑中的生长因子

基本信息

批准号：
6744387
负责人：
JAMES L. ROBERTS
金额：
$ 27.6万
依托单位：
UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
依托单位国家：
美国
项目类别：
财政年份：
1992
资助国家：
美国
起止时间：
1992-05-01 至 2006-04-30
项目状态：
已结题

项目摘要

Parkinson's disease is a progressive neurodegenerative disorder affecting the elderly, characterized by neurodegeneration of nigrostriatal domain neurons. Studies in our laboratory have been focused on identifying factors that are important for the survival and plasticity of dopamine neurons, which could protect them from degeneration or that are important for the survival and plasticity of dopamine neurons, which could protect them from degeneration or enhance compensatory responses. In response to MPTP induced toxicity, midbrain dopaminergic neurons exhibit some regenerative capacity, for young animals treated with the toxin are able to spontaneously recover. However, in the process of normal aging, this regenerative capacity of dopaminergic neurons becomes greatly reduced. We observed in response to MPTP induced degeneration of substantia nigra dopamine neurons in young mice, that there is a robust induction of IL-1 alpha which lasts for nearly two weeks and is associated with collateral sprouting of the ventral tegmental dopamine neurons. In contrast, to middle-aged mice we detected neither an induction of IL-1 alpha or collateral sprouting. To determine whether this induction of IL-1 alpha is necessary for lesion-induced sprouting to occur we are proposing to perform further experiments in mice in which the high affinity IL-1 alpha receptor has been genetically ablated. In further studies we obtained evidence that there may be changes in the extracellular matrix in middle-aged mice that may also contribute to reduced plasticity. Thus, we propose further studies to determine whether ectopic expression of IL-1, by retroviral infection of progenitor cells in middle-aged mice, can stimulate compensatory sprouting of dopamine neurons. In addition, to directly address whether the extracellular environment is play a role in reducing the ability of dopaminergic neurons to collateral sprout, we are proposing to graft fetal dopaminergic neurons into young and middle aged mice and compare the extent of fiber outgrowth. In specific regions of the CNS, neurons die and are being continuously replaced with newly developed neurons. It has recently become appreciated that neural stem cells are more widely dispersed than previously thought and can be induced to proliferate in response to brain injury. We have preliminary data showing that in response to MPTP, newly proliferated cells can be found in the substantia nigra which can have an un-committed phenotype. After longer periods of time after labeling our data suggests the possibility that these cells may eventually differentiate into dopamine neurons. Thus, we propose to establish whether new dopamine neurons are produced in response to injury or can be stimulated to differentiate by ectopically expressing cytokines, which are able to regulate neuronal.

帕金森病是一种影响老年人的进行性神经退行性疾病，其特征是黑质纹状体域神经元的神经退行性变。我们实验室的研究重点是确定对多巴胺神经元的生存和可塑性重要的因素，这可以保护它们免于退化，或者对多巴胺神经元的生存和可塑性很重要，这可以保护它们免于退化或增强代偿性回应。为了响应 MPTP 诱导的毒性，中脑多巴胺能神经元表现出一定的再生能力，因为用毒素治疗的幼年动物能够自发恢复。然而，在正常衰老过程中，多巴胺能神经元的再生能力大大降低。我们观察到，针对 MPTP 诱导的年轻小鼠黑质多巴胺神经元变性，IL-1 α 的强烈诱导持续了近两周，并且与腹侧被盖多巴胺神经元的侧支萌芽有关。相比之下，对于中年小鼠，我们既没有检测到 IL-1 α 的诱导，也没有检测到侧枝发芽。为了确定这种 IL-1 α 的诱导是否是损伤诱导发芽发生所必需的，我们建议在高亲和力 IL-1 α 受体已被基因消除的小鼠中进行进一步的实验。在进一步的研究中，我们获得的证据表明，中年小鼠的细胞外基质可能发生变化，这也可能导致可塑性降低。因此，我们建议进一步研究以确定通过逆转录病毒感染中年小鼠祖细胞而异位表达IL-1是否可以刺激多巴胺神经元的代偿性萌芽。此外，为了直接探讨细胞外环境是否在降低多巴胺能神经元侧枝萌发能力方面发挥作用，我们建议将胎儿多巴胺能神经元移植到中青年小鼠体内，并比较纤维生长的程度。在中枢神经系统的特定区域，神经元死亡并不断被新发育的神经元取代。最近人们认识到，神经干细胞的分布比以前想象的更广泛，并且可以因脑损伤而被诱导增殖。我们的初步数据表明，响应 MPTP，可以在黑质中发现新增殖的细胞，该细胞可能具有未定型的表型。经过较长时间的标记后，我们的数据表明这些细胞最终可能分化为多巴胺神经元。因此，我们建议确定新的多巴胺神经元是否因损伤而产生，或者是否可以通过异位表达的细胞因子刺激分化，这些细胞因子能够调节神经元。