COMPLEMENT AND INFLAMMATORY NEUROPATHY

补体和炎症性神经病

• 批准号: 2691772
• 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/2691772
• 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.

候选人是临床和基础科学培训的神经科医生 在炎症性神经病中。 她的先前研究重点是 补体在人类和动物模型中的致病作用 炎症性神经病。 此MCSDA提案探讨了截然不同的 在神经病中补体的作用，其潜在的有益作用 通过上调保护性补体调节性，SCHC恢复 蛋白质（CRP）以及细胞周期进入和进展的刺激。 这 探索这种新颖作用的基础，以补充免疫介导 神经病来自非神经元细胞的研究，这表明 该末端补体配合物（TCC）保护细胞免受随后的 通过补体攻击，上调保护性CRP并刺激DNA 合成和增殖；可能对恢复至关重要的事件 来自炎症性神经病。 尽管与 补体沉积，Schwann细胞（SCHC）似乎可以抵抗 细胞解析。 SCHC表达全部CRP，可能会授予 抵抗补体介导的胞解。而，亲戚 在髓鞘表面的保护性CRP的稀少可能是为了 对补充介导的损害的精致敏感性。 这个建议 专门研究：a）是否有补充的接触 通过上调表达来进一步减弱进一步补充介导的损害 保护性CRP，b）调节机制，这可能是 差异CRP表达并解释差分补体 SCHC身体和髓磷脂膜的敏感性，以及c）TCC是否 诱导和调节SCHC细胞周期的进入和进展，促进 恢复和最终再髓。我们建议调查这些 利用一系列体外SCC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确认这些作用。 这些研究的结果将扩展我们对重要作用的了解 补充，保护SCHC并触发从 炎症性神经病。 这些调查和必要的实验室 分子生物学，传输机制和细胞循环的培训 在主要导师穆恩博士和相关导师博士的领导下。 Koski和Edidin将提供丰富的跨学科培训 环境推动候选人的职业发展 保护性分子生物学领域的独立研究者 从炎症性神经病中恢复的机制。