COBRE: LSU: PROJ 3: SECRETED PHOSPHOLIPASES A2 PARTICIPATE IN NEURON SURVIVAL

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。本项目将明确分泌磷脂酶A2 （sPLA2s）在神经元信号传导和损伤中的意义。该项目的两个主要目标是：1)确定sPLA2s产生的脂质信使如何调节神经元的存活和功能，以及2)鉴定由sPLA2s调节的大脑中的基因表达。我们已经证明sPLA2s在体外和体内改变神经元的存活和功能。我们已经证明sPLA2s对谷氨酸刺激下神经元钙稳态和细胞损伤的影响。我们的假设是，sPLA2酶活性产生的脂质，如花生四烯酸和血小板活化因子，可能调节突触的神经元兴奋，从而改变大脑的生理和病理结果。在这里，我们将把细胞水平上的影响与体内结果（如学习和记忆）以及大脑细胞损伤联系起来。花生四烯酸和PAF将直接使用，以及纯化的sPLA2s，以调节神经元功能。该项目的第二个目标是确定大脑中sPLA2s引起的基因表达改变。这个目标将通过利用分子神经生物学核心模块来完成。神经元和星形胶质细胞的原代培养将是这项技术的理想选择，因为损伤和应激条件下的培养可以进行比较，以确定哪些基因被上调。用sPLA2s、PAF或花生四烯酸处理的实验动物脑组织也将被使用。因此，确定内源性sPLA2在神经元功能和损伤中的作用的目标将受益于分子神经生物学核心模块。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. This project will define the significance of secretory phospholipases A2 (sPLA2s) in neuronal signaling and injury. Two major goals of this project are to: 1) define how lipid messengers generated by sPLA2s modulate neuronal survival and function, and 2) to identify gene expression in the brain, modulated by sPLA2(s). We have shown that sPLA2s alter neuronal survival and function in vitro and in vivo. We have demonstrated effects of sPLA2s on neuronal calcium homeostasis and cell injury stimulated by glutamate. It is our hypothesis that lipids generated by sPLA2 enzyme activity, such as arachidonic acid and platelet-activating factor, may modulate neuronal excitation at the synapse, and thus alter physiological and pathological outcomes in the brain. Here we will correlate effects at the cellular level with in vivo outcomes such as learning and memory, as well as cell injury in the brain. Arachidonic acid and PAF will be used directly, as well as purified sPLA2s, to modulate neuronal function. A second goal of this project is to identify alterations in gene expression caused by sPLA2s in the brain. This goal will be accomplished by utilizing the Molecular Neurobiology Core Module. Primary cultures of neurons and astrocytes will be ideal for this technology, as cultures under injury and stress conditions can be compared to determine which genes are upregulated. Brain tissue from experimental animals treated with sPLA2s, PAF, or arachidonic acid will also be used. Thus, the goal of determining the role of endogenous sPLA2 in neuronal function and injury will benefit from the Molecular Neurobiology Core Module.