COMPLEMENT AND INFLAMMATORY NEUROPATHY

补体和炎症性神经病

• 批准号: 2891435
• 负责人: CHARLENE E HAFER-MACKO
• 金额: $ 10.21万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-07-01 至 2001-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2891435
• 关键词: CD antigens; DNA replication; SDS polyacrylamide gel electrophoresis; Schwann cells; biological signal transduction; cell cycle; cell membrane; cell migration; cell proliferation; complement pathway; cytolysis; disease /disorder model; gene expression; genetic regulation; glycosylation; immunocytochemistry; intracellular transport; laboratory rat; mixed tissue /cell culture; myelin; myelinopathy; neuritis; northern blottings; transcription factor; western blottings

The candidate is a Neurologist with clinical and basic science training in inflammatory neuropathy. Her prior research focused on the pathogenic effects of complement in human and animal models of inflammatory neuropathy. This MCSDA proposal explores a much different role for complement in neuropathy, its potential beneficial effects on SchC recovery through upregulation of protective complement regulatory proteins (CRP) and stimulation of cell cycle entry and progression. The basis for exploring this novel role for complement in immune-mediated neuropathy derives from studies in non-neuronal cells, which suggest that terminal complement complexes (TCC) protect cells from subsequent attack by complement, upregulate protective CRP, and stimulate DNA synthesis and proliferation; events which may be crucial for recovery from inflammatory neuropathy. In spite of demyelination associated with complement deposition, the Schwann cell (SchC) appears to resist cytolysis. SchC express the full array of CRP, which may confer resistance to complement mediated cytolysis. Whereas, the relative paucity of protective CRP on the surface of myelin may account for its exquisite sensitivity to complement mediated damage. This proposal specifically investigates: a) whether sublytic complement exposure attenuates further complement mediated damage by upregulating expression of protective CRP, b) the regulatory mechanisms, which may underlie the differential CRP expression and account for the differential complement susceptibility of the SchC body and myelin membranes, and c) whether TCC induced and regulate SchC cell cycle entry and progression, facilitating recovery and eventual remyelination. We propose to investigate these mechanisms utilizing a series of in vitro SchC and SchC/DRG co-culture model experiments. Parallel studies using an animal model of inflammatory neuropathy will be used to confirm these effects in vivo. Results of these studies will extend our knowledge of the important role of complement, protecting the Schc and triggering recovery from inflammatory neuropathy. These investigations and requisite laboratory training in molecular biology, transport mechanisms, and cell cycling under the principal mentor, Dr. Moon Shin, and associated mentors Drs. Koski and Edidin, will provide an enriched interdisciplinary training environment advancing the candidate's career toward becoming an independent investigator in the area of molecular biology of protective mechanisms underlying recovery from inflammatory neuropathy.

候选人是接受过临床和基础科学培训的神经科医生 在炎症性神经病中。 她之前的研究重点是 补体在人类和动物模型中的致病作用 炎症性神经病。 该 MCSDA 提案探索了一个非常不同的 补体在神经病中的作用，其潜在的有益作用 通过上调保护性补体调节来恢复 SchC 蛋白质（CRP）和细胞周期进入和进展的刺激。 这 探索补体在免疫介导中的新作用的基础 神经病源自对非神经元细胞的研究，这表明 末端补体复合物 (TCC) 可以保护细胞免受后续 补体攻击，上调保护性 CRP，并刺激 DNA 合成和增殖；对恢复可能至关重要的事件 来自炎症性神经病。 尽管脱髓鞘与 补体沉积，施万细胞 (SchC) 似乎会抵抗 细胞溶解。 SchC 表达了 CRP 的全部序列，这可能会赋予 对补体介导的细胞溶解的抵抗。鉴于，亲戚 髓磷脂表面缺乏保护性 CRP 可能是其原因 对补体介导的损伤具有敏锐的敏感性。 这个提议 专门研究： a) 是否有亚裂解补体暴露 通过上调表达进一步减轻补体介导的损伤 保护性 CRP，b) 调节机制，这可能是 差异 CRP 表达和差异补体的解释 SchC 体和髓磷脂膜的易感性，以及 c) 是否 TCC 诱导和调节 SchC 细胞周期进入和进展，促进 恢复并最终进行髓鞘再生。我们建议调查这些 利用一系列体外 SchC 和 SchC/DRG 共培养的机制 模型实验。使用动物模型的平行研究 炎症性神经病将用于在体内证实这些效应。 这些研究结果将扩展我们对其重要作用的认识 补体，保护 Schc 并触发恢复 炎症性神经病。 这些调查和必要的实验室 分子生物学、运输机制和细胞循环方面的培训 在首席导师 Moon Shin 博士和相关导师 Drs. Koski和Edidin将提供丰富的跨学科培训 环境促进候选人的职业生涯成为 保护性分子生物学领域的独立研究者 炎性神经病恢复的机制。