NEUROPATHOLOGY OF THE AGING SYMPATHETIC NERVOUS SYSTEM

描述：（改编自申请人的摘要）申请人已经表明 明显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尸检 人，并且具有神经轴突营养不良（NAD）的病理特征。 这些NAD类似于糖尿病患者中发生的NAD， 上级肠系膜和腹腔神经节，并似乎是选择性的一些 神经末梢的亚群，而完全保留其他。 他们 现在希望测试以下假设：1）NGF参与 年龄相关性NAD的发病机制;和2）年龄依赖性NAD由以下因素引起： 异常的突触可塑性，或者叠加在正常的突触可塑性上， 周转或作为损伤诱导的轴突再生和发芽的结果。 其具体目标是： 1. 为了使用老年小鼠模型和几种突变小鼠品系（Wallerian 退化延迟（奥拉）和衰老加速），以确定是否 NAD反映终末器官NGF的异常，对外源性 神经生长因子的药理学剂量，导致突触的最终丧失，涉及 神经肽含量确定的神经元或靶向终末器官，并干扰 突触功能。 2. 为了测试NAD是否可以通过强制再生在体内沉淀 交感神经元或其突触前末梢的出芽， 它们是否在独立于体内老化的培养系统中发育 环境。 3. 探讨老年人和糖尿病患者背根神经节中NAD的表达 表示血管周围交感神经轴突的病理性发芽和/或 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.