NEUROTROPHIC FACTORS IN SENSORY CELL ATROPHY AND RESCUE

感觉细胞萎缩和拯救中的神经营养因子

• 批准号: 2259909
• 负责人: JUDITH Mosinger OGILVIE
• 金额: $ 8.23万
• 依托单位: CENTRAL INSTITUTE FOR THE DEAF
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-09-16 至 1998-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2259909
• 关键词: atrophy; cell transplantation; cone cell; disease /disorder model; electron microscopy; eye transplantation; immunocytochemistry; laboratory mouse; light microscopy; molecular pathology; neurobiology; neurotrophic factors; organ culture; retina degeneration; retinal pigment epithelium; rod cell

Trophic interactions among sensory cells, neurons and supporting cells play an important role in the development and maintenance of sensory function. Loss of any one component may lead to atrophy of other cells, resulting in sensory deficit. Photoreceptor loss is the primary cause of visual impairment in several retinal degenerative diseases such as retinitis pigmentosa and macular degeneration. Sensory impairment resulting from degeneration of neural tissue was once considered irreversible. New possibilities are being raised as understanding of biochemical and molecular mechanisms of photoreceptor degeneration increases in animal models such as the rd (retinal degeneration) mouse. Furthermore, recent neural transplantation efforts related to degenerative brain diseases such as Parkinson's, Huntington's and Alzheimer's have stimulated research on neurosensory transplantation. Recently, this lab has presented evidence that normal photoreceptors transplanted from healthy mice can rescue cone photoreceptors in the rd mouse. This is the first instance of neurosensory rescue in an animal model relevant for a human sensory dystrophy. This proposal is based on the hypothesis that normal rod photoreceptors have a trophic effect on cone photoreceptors and supporting cells such as retinal pigment epithelium (RPE). The long term goal of this research is to develop an understanding of the molecular changes that underlie the secondary degeneration of cones and RPE in the rd mouse and to develop methods to prevent or minimize this loss. To achieve these goals, (I) normal mouse photoreceptors will be transplanted into the rd mouse followed by statistical and morphometric analysis to measure the effect of the transplanted cells on the survival of host cells, (2) an organ culture system will be developed with normal and dystrophic retinal tissue to simulate the in vivo model and (3) the organ culture system will be manipulated with trophic factors known to mediate sensory cell growth to better understand what molecular mechanisms are involved in maintenance and survival of sensory and supporting cells. The proposed re-entry training program builds on previous training by reestablishing both current knowledge of retinal research and technical expertise in light and electron microscopy. New training will emphasize knowledge of neurotrophic factors and cell and organ culture techniques. These elements will be use to build a research program focusing on trophic interactions between neural and support cells in the visual system.

感觉细胞、神经元和支持细胞之间的营养相互作用 对感觉的发育和维持起着重要作用 功能。任何一种成分的丢失都可能导致其他细胞萎缩， 导致感觉缺失。光感受器丧失是造成这种现象的主要原因 多种视网膜退行性疾病导致的视力障碍，例如 视网膜色素变性和黄斑变性。感觉障碍 曾被认为是神经组织退化造成的 不可逆转的。随着对以下问题的理解，新的可能性正在被提出 光感受器变性的生化和分子机制 动物模型如 rd（视网膜变性）小鼠的增加。 此外，最近与退行性病变相关的神经移植工作 帕金森氏症、亨廷顿氏症和阿尔茨海默氏症等脑部疾病 刺激了神经感觉移植的研究。近日，该实验室 已提出证据表明正常光感受器移植自 健康小鼠可以挽救 rd 小鼠的视锥细胞感光器。这是 在与相关动物模型中进行神经感觉救援的第一个实例 人类感觉障碍。 该提议基于以下假设：正常杆状光感受器 对视锥细胞和支持细胞有营养作用，例如 视网膜色素上皮（RPE）。这项研究的长期目标是 加深对潜在分子变化的理解 rd 小鼠视锥细胞和 RPE 继发性变性并发育 防止或减少这种损失的方法。为了实现这些目标，（一） 正常小鼠的光感受器将被移植到rd小鼠体内 然后进行统计和形态分析来衡量效果 移植细胞对宿主细胞存活的影响，（2）器官培养 系统将利用正常和营养不良的视网膜组织来开发 模拟体内模型和（3）器官培养系统 用已知介导感觉细胞生长的营养因子进行操纵 更好地了解维护中涉及哪些分子机制 以及感觉细胞和支持细胞的存活。 拟议的重返训练计划以之前的训练为基础 重建当前的视网膜研究知识和技术 光学和电子显微镜方面的专业知识。新的培训将强调 神经营养因子以及细胞和器官培养技术的知识。 这些要素将用于建立一个以营养为重点的研究计划 视觉系统中神经细胞和支持细胞之间的相互作用。