MICROMAPPING OF LEAD INDUCED CHANGES TO NMDA RECEPTORS

铅引起的 NMDA 受体变化的微图谱

• 批准号: 6524699
• 负责人: DIANA Leslie PETTIT
• 金额: $ 10.66万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-08-02 至 2004-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6524699
• 关键词: NMDA receptors; calcium flux; hippocampus; immunocytochemistry; laboratory rat; lead; long term potentiation; neurophysiology; neurotoxicology; protein localization; receptor expression; voltage /patch clamp

DESCRIPTION (Taken from the Candidate's Abstract) The widespread use of lead has made lead exposure a serious environmental and occupational hazard. Children are particularly vulnerable to the effects of lead and exposure can cause serious cognitive and behavioral deficits. Although lead is a known environmental neurotoxin, the physiological bases of this toxicity remain unclear. However, evidence suggests that the NMDA-type glutamate receptor function is down-regulated by lead, and this down regulation attenuates long-term potentiation (LTP), a cellular correlate of learning. Recent studies of downregulation have used binding assays and immunocytochemistry to show that binding of agonist is reduced after lead treatment. While these studies provide valuable information, they are not functional assays of receptors in intact tissue. The candidate will determine how lead modifies NMDA receptor function with a novel, high resolution method of localizing and characterizing receptor function. This method uses local photolysis of caged agonists to isolate 3 um membrane sections in living cells within brain slices. The candidate will combine whole-cell voltage clamp recordings, local photolysis, and calcium imaging to examine the effect of NMDA receptor downregulation on long-term potentiation and long-term depression. She hypothesizes that lead decreases NMDA receptor function by decreasing expression of functional receptors, changing receptor subunit composition, and altering calcium permeability, which attenuates LTP and LTD. These experiments will provide a basis for examination of the downstream processes initiated by receptor activation.

描述（摘自候选人的摘要） 铅的广泛使用使铅暴露成为严重的环境问题 职业危害。 儿童特别容易受到以下因素的影响 铅和接触会导致严重的认知和行为缺陷。 尽管铅是一种已知的环境神经毒素，但其生理基础 这种毒性尚不清楚。 然而，有证据表明 NMDA 型 铅会下调谷氨酸受体功能，并且这种下调 调节会减弱长时程增强 (LTP)，这是一种细胞相关性 学习。 最近的下调研究使用了结合测定法和 免疫细胞化学显示铅后激动剂的结合减少 治疗。 虽然这些研究提供了有价值的信息，但它们并没有 完整组织中受体的功能测定。 候选人将决定 铅如何通过一种新颖的高分辨率方法改变 NMDA 受体功能 定位和表征受体功能。 该方法使用本地 笼式激动剂光解以分离活细胞中 3 um 膜切片 在大脑切片内。 候选者将结合全细胞电压钳 录音、局部光解和钙成像来检查效果 NMDA 受体下调对长时程增强和长时程的影响 沮丧。 她推测铅会通过以下方式降低 NMDA 受体功能： 功能受体表达减少，受体亚基改变 成分，并改变钙渗透性，从而减弱 LTP 和 LTD。 这些实验将为下游的检验提供依据。 由受体激活引发的过程。