GROWTH FACTORS IN THE ADULT AND AGING BRAIN

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区神经元的神经退行性变。我们实验室的研究一直集中在寻找对多巴胺神经元的生存和可塑性至关重要的因素，这些因素可以保护多巴胺神经元免于变性，或者对多巴胺神经元的生存和可塑性重要，这些因素可以保护多巴胺神经元免于变性或增强代偿反应。在MPTP诱导的毒性作用下，中脑多巴胺能神经元表现出一定的再生能力，幼年动物经MPTP处理后能够自发恢复。然而，在正常衰老的过程中，多巴胺能神经元的这种再生能力会大大降低。在MPTP诱导幼鼠黑质多巴胺神经元变性的反应中，我们观察到IL-1α的强烈诱导，这种诱导持续了近两周，并与腹侧被盖多巴胺神经元的侧枝萌发有关。相反，对于中年小鼠，我们既没有检测到IL-1α的诱导，也没有检测到侧枝萌发。为了确定这种IL-1α的诱导是否是病变诱导发芽所必需的，我们建议在高亲和力IL-1α受体已被基因消融的小鼠身上进行进一步的实验。在进一步的研究中，我们获得了中年小鼠细胞外基质可能发生变化的证据，这可能也是导致可塑性降低的原因之一。因此，我们建议进行进一步的研究，以确定通过逆转录病毒感染中年小鼠的祖细胞异位表达IL-1是否可以刺激多巴胺神经元的代偿性萌发。此外，为了直接解决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青年和中年小鼠身上，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，并不断被新生的神经元取代。最近人们认识到，神经干细胞比以前认为的更广泛地分散，并且可以被诱导增殖以应对脑损伤。我们有初步的数据显示，作为对MPTP的反应，可以在黑质中发现新的增殖细胞，这些细胞可能具有未确定的表型。在标记了更长的时间后，我们的数据表明，这些细胞最终可能会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对损伤做出反应，还是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。

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.