ROLE INTRACELLULAR Ca2+ CONCENTRATION IN DEVELOPMENT OF ALZHEIMER'S DISEASE

n -酰基乙醇胺（NAEs）是一种有效的生物活性脂质信号物质，在哺乳动物生理中具有多种作用。我们建议研究植物源性NAEs作为包括阿尔茨海默病在内的神经系统疾病的现有神经保护治疗的潜在替代品和补充。我们的初步数据表明，NAEs调节细胞内钙通道的功能，从而调节细胞内钙信号传导。nae是天然存在的化合物，因此存在对这些化合物的代谢和清除过程，从而降低了nae相关毒性的可能性。该应用的中心假设是NAEs对神经元起保护作用。NAEs介导的神经保护机制将在分子水平、神经细胞系、原代神经元培养和体内作为神经毒性损伤和神经变性模型进行分析和评估。特别是，NAEs的作用将被评估其预防细胞死亡和引发神经保护相关信号通路的能力。

N-Acylethanolamines (NAEs) are potent, bioactive lipid signaling substances with diverse roles in mammalian physiology. We propose to investigate plant-derived NAEs functioning both as potential alternatives and supplements to currently existing neuroprotecting treatments for neurological disorders including Alzheimer's disease. Our preliminary data indicate that NAEs regulate the function of intracellular calcium channels allowing modulation of intracellular calcium signaling. NAEs are naturally occurring compounds, and therefore there are in place metabolic and clearance processes for these compounds lessening the likelihood of NAE-associated toxicities. The central hypothesis of this application is that NAEs exert protective effects on neurons. The mechanisms of neuroprotection mediated by NAEs will be analyzed and evaluated at the molecular level, in neuronal cell lines, primary neuronal cultures and in vivo as models of neurotoxic insults and neurodegeneration. In particular, the effect of NAEs will be evaluated for their ability to prevent cell death and elicit neuroprotection-related signaling pathways. The specific aims are: 1) Analyze the modulation of biophysical and pharmacological characteristics of intracellular calcium channels by NAEs; 2) to identify and measure the contribution of NAE mediated responses to intracellular Ca 2+ signaling of neurons; 3) to determine the neuroprotective effects of NAEs in neuronal cell lines as models of neurotoxic insults and neurodegeneration; 4) to identify the neuroprotective signal transduction pathways elicited by NAEs in primary neuronal cultures of the hippocampus as models of neurotoxic insults and neurodegeneration.; 5) to determine the effects of NAEs on ischemic damage in an animal model of stroke. Experiments will use a combination of biochemistry, electrophysiology, optical imaging of intracellular Ca 2+ concentrations, analyses of changes in intracellular signaling and neuroprotection assays. The overall goal of this study is to provide the necessary foundation for the development of novel alternative or supplemental treatments for neurodegeneration in Alzheimer's disease.