VASCULAR, FREE RADICAL AND DNA CHANGES IN AGED COCHLEAS

老年耳蜗的血管、自由基和 DNA 变化

• 批准号: 2124572
• 负责人: Michael D. Seidman
• 金额: $ 9.16万
• 依托单位: HENRY FORD HEALTH SYSTEM
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-08-01 至 1999-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2124572
• 关键词: aging; allopurinol; cochlea; cochlear microphonic potentials; ear pharmacology; erythrocytes; free radical oxygen; free radical scavengers; gene deletion mutation; hearing; hemodynamics; histopathology; laboratory rat; light microscopy; microcirculation; mitochondrial DNA; oxidative stress; peroxidation; polymerase chain reaction; presbycusis; sensorineural hearing loss; superoxide dismutase; vascular endothelium permeability

The long term objectives of this research protocol are to: 1) Investigate age related cochlear microcirculatory changes; 2) study molecular biologic changes in age related hearing loss (presbycusis), and 3) attempt to attenuate presbycusis via free oxygen radical scavenging and blocking agents. It has been demonstrated that in the elderly population there is significantly decreased flow within the circulatory system. This proposal will investigate related changes in cochlear vascular permeability, red blood cell velocity, and vessel diameter that may account for this reduction in blood flow. Intravital microscopic techniques will be employed to asses cochlear vascular changes. Prolonged periods of reduced blood flow such as those accompanying aging lead to the formation of tissue damaging free oxygen radicals (FOR). FORs have been implicated as mediators in mitochondrial DNA damage including the generation of mitochondrial DNA deletions (mt DNA del). MtDNA del have associated with cellular and tissue dysfunction, senescence and death. This sequence of events is the foundation of the membrane hypothesis of aging (MHA). The second series of experiments is designed to assess age related changes in cochlear mtDNA del. Polymerase chain reaction will be used to assess changes in cochlear mtDNA del. Studies have demonstrated that loss of auditory sensitivity following ischemia/reprefusion injury can be attenuated by blockers of FOR production (allopurinol), scavengers of FOR (Superoxide-dismutase) and lipid peroxidation inhibitors (Tirilazad mesylate and U74389F) (Seidman et al, 1991, a,b; Seidman et al, 1993). These studies support the role of FOR induced cochlear damage. The third series of experiments will assess the effect of allopurinol ( a blocker and potentially a scavenger of FORs), superoxide-dismutase (SOD a scavenger of FORs), and U74389F (a lazaroid which acts by inhibiting lipid peroxidation), on age related hearing loss. Auditory brainstem response a (ABR) will be used to assess auditory sensitivity. The health relatedness of this project is realized by considering the more than 30 million Americans who suffer from significant sensori-neural hearing loss. As our population ages this number increases rapidly. In the United States today, 23% of the population, between 65 and 75 years, are affected by hearing loss and 40 % of the population, 75 years and above, is affected. In 1980 it was estimated that 11% of the population was 76 years or older. This number is expected to increase to nearly 21% by the year 2030.

该研究方案的长期目标是：1）调查 与年龄相关的耳蜗微循环变化； 2）研究分子 与年龄相关的听力损失的生物学变化（长期）和3） 尝试通过自由氧自由基清除和 阻止代理。 已经证明，在老年人口中 循环系统内的流量显着下降。 这 提案将研究人工耳蜗血管的相关变化 渗透率，红细胞速度和血管直径可能 解释了血流的减少。 插入式显微镜 技术将用于驴的耳蜗血管变化。 长时间减少的血液流量，例如伴随衰老的人 导致组织破坏自由基自由基的组织形成。 在线粒体DNA损伤中，福克斯被认为是介体 包括生成线粒体DNA缺失（MT DNA DEL）。 mtdna del与细胞和组织功能障碍有关， 衰老和死亡。 一系列事件是 衰老的膜假设（MHA）。 第二系列实验是 旨在评估人工耳蜗MTDNA DEL的年龄变化。 聚合酶 链反应将用于评估人工耳蜗MTDNA DEL的变化。 研究表明，随后的听觉敏感性丧失 缺血/再灌注损伤可能会被阻止者衰减 生产（别嘌醇），用于（超氧化物抗酶）和 脂质过氧化抑制剂（Tirilazad Mesylate和U74389F）（Seidman 等，1991，a，b; Seidman等，1993）。 这些研究支持该角色 用于诱发的人工耳蜗损伤。 第三系列实验将 评估别嘌呤醇的效果（阻滞剂，并可能是清道夫 fors），超氧化物抗抗性酶（SOD的福克斯）和u74389f（a 通过抑制脂质过氧化作用的拉扎类 听力损失。 听觉脑干响应A（ABR）将用于评估 听觉敏感性。 通过考虑 超过3000万美国人患有大量的传感器神经 听力损失。 随着人口的年龄，这个数字迅速增加。 在 今天，美国，人口的23％，在65至75年之间， 受听力损失的影响和40％的人口，75年， 上面受影响。 1980年估计有11％的人口 76岁以上。 这个数字预计将增加到近21％ 到2030年。