Mechanisms of Aging in the Somatosensory System

此应用程序结合了三个已建立的 感官生物学实验室，研究细胞、分子和 躯体感觉系统中年龄相关变化的生理方面。这个 实验解决了项目公告(99-123)的目标，标题为 老化感觉：多个感觉系统之间的关系。长期目标 这项研究的目的是确定导致 感觉神经元及其末端器官的退化，并确定 调节皮肤提供的营养支持水平可以缓解 与年龄相关的感觉障碍的发生和发展。感受到了 触摸、疼痛和温度通过不同的形态和 位于皮肤中的电生理学上不同的机械感官末端。 这些末端由感觉神经元和专门的末端器官组成， 例如，默克尔复合体、迈斯纳小体，作为一种 衰老的后果。失去神经支配会导致触觉减少。 对工作表现和质量有重大影响的敏感度 对于老年人来说，这是生活的一部分。研究表明，三叉神经核的萎缩是 以神经元敏感性降低和完整性降低为特征的 和/或外围终端的数量。我们假设这些退化的 变化与生长因子信号有关，特别是对于 神经营养因子NT3和BDNF。过表达NT3或NT3的转基因小鼠的研究 皮肤中的脑源性神经营养因子表明，它们以非常特殊的方式发挥作用，以增强 感觉末梢的发育、维持和生理特性。在这 我们提出的项目是为了确定NT3和BDNF如何影响形态， 体外培养感觉神经元的细胞和生理特性 皮肤/神经/脊髓准备。该制剂将用于鉴定 大鼠皮肤神经元的生理特性和化学表型 幼年和老年小鼠以及皮肤中过度表达NT3或BDNF的小鼠。在……里面 这样，我们将在中定义敏感度和响应属性的差异 与神经元表型和年龄的关系，并决定营养因子如何改变 这些属性。为了探索神经元在衰老系统中失去敏感性的原因， 我们将分析被认为是中介的通道受体蛋白的表达 幼年和老年小鼠生理特征神经元的机械感觉 并确定它们的表达是否响应于 NT3或BDNF的表达。实验设计将使用免疫细胞化学， 免疫印迹、逆转录-聚合酶链式反应和原位杂交分析RNA和蛋白质 Expression，一种体外皮肤/神经/脊髓生理制剂 结构性或诱导性表达的分析和转基因小鼠 皮肤中NT3和BDMF的水平增加。

This application combines the expertise of three established laboratories in sensory biology to investigate the cellular, molecular and physiological aspects of age-related changes in the somatosensory system. The experiments address the goals of the Program Announcement (99-123) titled The Aging Senses: Relationships Among Multiple Sensory Systems. The long-term goal of this research is to identify the cellular mechanisms that lead to degeneration of sensory neurons and their end organs and determine whether modulating the level of trophic support provided by the skin can alleviate the onset and progression of age-related deficits in sensation. Sensations of touch, pain and temperature are transmitted by a variety of morphologically and electrophysiologically distinct mechanosensory endings located in the skin. These endings are comprised of sensory neurons and specialized end organs, e.g., Merkel complexes, Meissner corpuscles, that undergo degeneration as a consequence of aging. The loss of innervation causes reduced tactile sensitivity that can have significant impact on job performance and the quality of life for elderly individuals. Studies have shown that atrophy in the PNS is characterized by decreased neuron sensitivity and reduction in the integrity and/or number of peripheral terminals. We hypothesize these degenerative changes are related to growth factor signaling, in particular for the neurotrophins NT3 and BDNF. Studies of transgenic mice that overexpress NT3 or BDNF in the skin have shown they act in very specific manners to enhance sensory ending development, maintenance and physiological properties. In this project we propose to identify how NT3 and BDNF affect the morphological, cellular and physiological properties of sensory neurons using an ex vivo skin/nerve/spinal cord preparation. This preparation will be used to identify the physiological properties and chemical phenotype of cutaneous neurons of young and old mice and mice that overexpress either NT3 or BDNF in the skin. In this way we will define differences in sensitivity and response properties in relation to neuron phenotype and age, and determine how trophic factors alter these properties. To explore why neurons lose sensitivity in the aging system, we will analyze the expression of channel receptor proteins thought to mediate mechanosensation in physiologically characterized neurons of young and old mice and determine whether their expression is modulated in response to elevation in NT3 or BDNF expression. The experimental design will use immunocytochemistry, immunoblotting, RT-PCR and in situ hybridization to analyze RNA and protein expression, an ex vivo skin/nerve/spinal cord preparation for physiological analysis and transgenic mice that either constitutively or inducibly express increased levels of NT3 nr BDMF in the skin.