NEUROPATHOLOGY OF THE AGING SYMPATHETIC NERVOUS SYSTEM

描述：(改编自申请者摘要)申请者已表明 显著增大的终末轴突和突触聚集在 老年实验动物的交感神经系统和身体解剖 具有神经轴突性营养不良(NAD)的病理特征。 这些NAD类似于发生在糖尿病患者中的那些，有倾向于 肠系膜上神经节和腹膜上神经节，似乎对某些神经节有选择性 神经末梢的亚群，而完全放过其他神经末梢。他们 现在我想检验以下假设：1)NGF参与 与年龄相关的NAD的发病机制；2)年龄相关性NAD的原因 突触可塑性异常，要么叠加在正常突触上 周转或由于损伤导致的轴突再生和萌发。 他们的具体目标是： 1.利用衰老小鼠模型和几个突变小鼠品系(Weller Ian) 退变延迟(OLA)和衰老加速)以确定 NAD反映了终末器官NGF的异常，对外源性很敏感 NGF的药理剂量，最终导致突触丢失，涉及 确定神经肽含量或靶向内脏的神经元，并进行干扰 具有突触功能。 2.检测NAD是否可以通过强制再生在体内沉淀 以及交感神经元或其突触前终末的萌发，以及 它们是否在独立于体内衰老的培养系统中发育 周围的环境。 3.探讨NAD在增龄和糖尿病人背根神经节中的作用 代表血管周围交感神经轴突和/或病理性发芽 背根神经节神经元。

DESCRIPTION: (Adapted from Applicant's Abstract) The applicants have shown that distinctive markedly enlarged terminal axons and synapses accumulate in the sympathetic nervous systems of aged experimental animals and autopsied humans, and have the pathologic features of neuraxonal dystrophy (NAD). These NAD resemble those that occur in diabetics, have a predilection for superior mesenteric and celiac ganglia, and appear to be selective for some subpopulations of nerve terminals, while completely sparing others. They now wish to test the following hypotheses: 1) that NGF participates in pathogenesis of age-related NAD; and 2) that age-dependent NAD result from abnormal synaptic plasticity, either superimposed on normal synaptic turnover or as a result of injury-induced axonal regeneration and sprouting. Their specific aims are: 1. To use the aged mouse model and several mutant mouse strains (Wallerian degeneration-delayed (Ola) and senescence accelerated) to determine whether NAD reflect an abnormality of end-organ NGF, are sensitive to exogenous pharmacologic doses of NGF, result in eventual loss of synapses, involve neurons of defined neuropeptide content or targeted endorgans, and interfere with synaptic function. 2. To test whether NAD can be precipitated in vivo by forced regeneration and sprouting of sympathetic neurons or their presynaptic terminals, and whether they develop in a culture system independent of the aged in vivo milieu. 3. To determine whether NAD in aging and diabetic human dorsal root ganglia represents pathologic sprouting of perivascular sympathetic axons and/or dorsal root ganglion neurons.