Altered Nociception and Neuronal Migration in the Dorsal Horn of Reeler Mice

Reeler 小鼠背角伤害感受和神经元迁移的改变

• 批准号: 0518714
• 负责人: Patricia Phelps
• 金额: $ 45万
• 依托单位: University of California-Los Angeles
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-01 至 2009-07-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=0518714&HistoricalAwards=false
• 关键词: Altered; Nociception; Neuronal; Migration; Dorsal

Principal Investigator: Dr. Patricia E. PhelpsTitle: Altered nociception and neuronal migration in the dorsal horn of reeler mice Grant Number: IOB-0518714The reeler mouse (a mouse whose reeler gene is defective) is characterized by motor coordination defects and tremors that result from errors in cell migration during development of the cerebral cortex and cerebellar cortex, both in the brain. Reelin, the protein missing in reeler mice, binds to lipoprotein receptors (VLDL/ApoE2), leading to phosphorylation of the intracellular protein Disabled-1 (Dab1). Mice missing either Dab1 or VLDL/ApoE2 receptors have anatomical and behavioral defects virtually identical to those of reeler mice, as these three molecules function in a common signaling pathway.Dr. Phelps's lab has provided the first evidence that reeler mutants also have profound sensory defects, including mechanical insensitivity and increased thermal sensitivity. The first aim of this proposal is to determine if mice lacking Dab1 or VLDL/ApoE2 receptor also have defects in pain sensation. The second aim is to study the migratory errors that cause the abnormal sensory processing. Preliminary results suggest that part of the spinal cord (the superficial dorsal horn) in reeler mice contains mispositioned neurons. To prove that these migratory errors are caused by Reelin deficiency, the Reelin signaling pathway will be blocked with the goal of recapitulating the migratory errors in a culture dish. To further link the defects in pain processing with anatomical rearrangements, experiments will be conducted to determine which neurons along the pain processing pathway are responsible for the sensory defects. These studies will focus on the primary sensory neurons that detect pain and their targets in the dorsal horn of the spinal cord. Finally, the basic migratory patterns that establish dorsal horn lamination will be examined. This proposal continues activities initially funded by an NSF Early Career Award. Integration of research and teaching activities includes teaching an undergraduate class on the principles of nervous system development and disseminating multimedia material developed for this class in the California Digital Library. Additionally, minority students have and will continue to conduct research in the Phelps' laboratory.

主要研究者：Patricia E. Phelps标题：reeler小鼠背角的伤害感受改变和神经元迁移批准号：IOB-0518714 reeler小鼠（一种reeler基因缺陷的小鼠）的特征是运动协调缺陷和震颤，这是由于大脑皮层和小脑皮层发育期间细胞迁移错误造成的。在reeler小鼠中缺失的蛋白质Reelin与脂蛋白受体（VLDL/ApoE 2）结合，导致细胞内蛋白Disabled-1（Dab 1）磷酸化。 缺失Dab 1或VLDL/ApoE 2受体的小鼠具有与reeler小鼠几乎相同的解剖学和行为缺陷，因为这三种分子在共同的信号通路中发挥作用。Phelps博士的实验室提供了第一个证据，证明reeler突变体也具有严重的感觉缺陷，包括机械不敏感性和增加的热敏感性。该建议的第一个目的是确定缺乏Dab 1或VLDL/ApoE 2受体的小鼠是否也具有痛觉缺陷。 第二个目的是研究引起异常感觉加工的迁移错误。 初步结果表明，在reeler小鼠的部分脊髓（浅层背角）包含错位的神经元。为了证明这些迁移错误是由Reelin缺乏引起的，将阻断Reelin信号通路，目的是在培养皿中重现迁移错误。为了进一步将疼痛处理中的缺陷与解剖学重排联系起来，将进行实验以确定疼痛处理通路上的哪些神经元沿着负责感觉缺陷。这些研究将集中在初级感觉神经元检测疼痛和他们的目标在脊髓背角。最后，将检查建立背角分层的基本迁移模式。该提案继续最初由NSF早期职业奖资助的活动。研究和教学活动的整合包括教授神经系统发育原理的本科课程，并在加州数字图书馆传播为这门课开发的多媒体材料。此外，少数民族学生已经并将继续在菲尔普斯实验室进行研究。