MOLECULAR GERONTOLOGY OF THE HUMAN OLFACTORY SYSTEM

人类嗅觉系统的分子老年学

• 批准号: 6533808
• 负责人: MARILYN GETCHELL
• 金额: $ 19.83万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-01 至 2004-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6533808
• 关键词: Alzheimer's disease; aging; antioxidants; apoptosis; clinical research; human tissue; immunocytochemistry; neural degeneration; olfactions; olfactory lobe; oxidative stress; postmortem; respiratory epithelium

The human olfactory mucosa, olfactory bulb, and anterior olfactory nucleus exhibit cellular, molecular, and functional changes as a correlate of aging and of Alzheimer's disease. Among these changes are both peripheral and central neurodegeneration. The long term objectives of this research are to gain insight into the cellular and molecular mechanisms that induce neurodegeneration in the neurons of the olfactory epithelium, olfactory bulb, and anterior olfactory nucleus as humans age and as a consequence of Alzheimer's disease, and to identify measures of cellular and molecular olfactory neuropathology related to Alzheimer's disease that may correlate with central neuropathological criteria and clinical tests of dementia. The specific aims of this proposal are to investigate the impact of oxidative stress on olfactory neurons during the course of healthy aging and in patients with Alzheimer's disease by investigating antioxidant enzyme levels, molecular indicators of oxidative damage, and apoptotic neuronal death. These studies will utilize human postmortem olfactory tissues from clinically well-characterized non-demented elderly subjects and from patients with Alzheimer's disease recruited by the NIH/NIA-funded Alzheimer's Disease Research Center at the Sanders-Brown Center on Aging. Tissues will be probed with immunohistochemical and molecular reagents that are indicative of exposure to sources of oxidative stress and of apoptotic cell death in order to identify and characterize age- and Alzheimer's disease-related changes among the young-old, old-old, and oldest-old, and in age-matched patients with Alzheimer's disease. Immunohistochemistry will be used to localize cellular changes, and quantitative biochemical/molecular analyses and stereological techniques will be used to assess their severity and to compare between groups. With the numbers of the oldest-old growing more rapidly than other segment of the population, and with age being a major risk factor for Alzheimer's disease, insight into neurodegenerative mechanisms that contribute to olfactory dysfunction may be of translational and therapeutic value in future patient-oriented research.

人类嗅粘膜、嗅球和前嗅核表现出细胞、分子和功能变化，这些变化与衰老和阿尔茨海默病相关。这些变化包括外周和中枢神经变性。 这项研究的长期目标是深入了解随着人类年龄的增长和阿尔茨海默病的结果，诱导嗅上皮、嗅球和前嗅核神经元神经变性的细胞和分子机制，并鉴定与阿尔茨海默病相关的细胞和分子嗅觉神经病理学的测量，其可能与中枢神经病理学标准和临床痴呆症的测试 该提案的具体目的是调查的影响，在健康的老龄化过程中，并在阿尔茨海默氏病患者的嗅觉神经元的氧化应激通过调查抗氧化酶水平，氧化损伤的分子指标，和神经元凋亡死亡。 这些研究将利用来自临床特征良好的非痴呆老年受试者和由NIH/NIA资助的Sanders-Brown老龄中心阿尔茨海默病研究中心招募的阿尔茨海默病患者的人类死后嗅觉组织。 组织将用免疫组织化学和分子试剂进行探测，这些试剂指示暴露于氧化应激和凋亡细胞死亡的来源，以识别和表征年龄和阿尔茨海默病相关的变化，包括老年人，老年人和最年长的老年人以及年龄匹配的阿尔茨海默病患者。 免疫组织化学将用于定位细胞变化，定量生化/分子分析和体视学技术将用于评估其严重程度并进行组间比较。随着年龄最大的老年人的数量比其他人群增长得更快，年龄是阿尔茨海默病的主要风险因素，深入了解导致嗅觉功能障碍的神经退行性机制可能具有转化和治疗价值在未来以患者为导向的研究中。