AGING, BRAIN MEMBRANE CHOLESTEROL DOMAINS AND CALCIUM

衰老、脑膜胆固醇域和钙

• 批准号: 2001459
• 负责人: WELLINGTON GIBSON WOOD
• 金额: $ 26.56万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-09-30 至 1998-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2001459
• 关键词: aging; brain metabolism; calcium channel blockers; calcium flux; calcium indicator; calcium transporting ATPase; cell membrane; chemical structure; cholesterol; fatty acid binding protein; homeostasis; laboratory mouse; lipid metabolism; membrane lipids; molecular site; phospholipids; phosphorylation; protein sequence; sphingomyelins; sulfonate; synapses; synaptosomes; thin layer chromatography; western blottings

The overall goals of this grant application are to study potential mechanisms associated with regulation of neuronal transbilayer and lateral cholesterol domains and how cholesterol domains interact with calcium homeostasis in neuronal membranes of different age groups of mice. We have recently shown in synaptic plasma membranes (SPM) of young C57BL mice, that the two membrane leaflets are asymmetric in their fluidity and cholesterol distribution. Membrane cholesterol was also found to be located in exchangeable and non-exchangeable pools and membrane cholesterol domains could be altered by hydrolysis of sphingomyelin that also altered intracellular calcium. Preliminary data from out laboratory showed that the asymmetry of fluidity between the two SPM leaflets observed in 6 month old animals was significantly reduced in SPM of 28 month old animals and that the exofacial leaflet was more affected as compared to the cytofacial leaflet. Previous studies on membrane lipid structure in different age groups of animals have examined changes in the average fluidity of the membrane lipid structure, whereas other studies have not observed age differences. We propose that increasing age is associated with marked changes in membrane lipid structure but that such changes are occurring in specific lipid domains and changes in lipid domains contribute to modification of calcium homeostasis that has been previously shown to differ with increasing age. The proposed experiments will focus on SPM and synaptosomes of 4, 16, and 28 month old C57BL/NNia mice. The specific aims of this application are to: 1) determine transbilayer distribution of cholesterol in the SPM exofacial and cytofacial leaflets; 2) examine cholesterol lateral domains in SPM; 3) phospholipid distribution in SPM exofacial and cytofacial leaflets; 4) involvement of sphingomyelin in regulation of cholesterol domains; 5) brain sterol carrier proteins and regulation of cholesterol domains; and 6) cholesterol domains and presynaptic calcium. It is our working hypothesis that aging impairs the capacity of the membrane to regulate cholesterol domains and such changes in cholesterol domains modify neuronal calcium.

该赠款申请的总体目标是研究潜力 与神经元跨贝和侧向调节相关的机制 胆固醇结构域以及胆固醇结构域如何与钙相互作用 小鼠不同年龄组的神经元膜中的稳态。我们有 最近在年轻C57BL小鼠的突触质膜（SPM）中显示 这两个膜小叶的流动性不对称和 胆固醇分布。膜胆固醇也被发现是 位于可交换和不可交换的水池和膜 胆固醇结构域可能会因鞘磷脂的水解而改变 还改变了细胞内钙。 OUT实验室的初步数据 表明两个SPM小叶之间的流动性不对称性 在6个月大的动物中观察到的SPM显着降低了28个 一个月大的动物，外叶传单受到了更大的影响 与胞质小叶相比。先前关于膜脂质的研究 不同年龄段的动物的结构检查了 膜脂质结构的平均流动性，而其他研究 没有观察到年龄差异。我们建议增长的年龄是 与膜脂质结构的明显变化相关，但 在特定的脂质结构域中发生变化，脂质变化 域有助于改变钙稳态 先前显示的随着年龄的增长而有所不同。提出的实验 将专注于4、16和28个月大的C57BL/NNIA的SPM和突触体 老鼠。本应用程序的具体目的是：1）确定 胆固醇在SPM外生中的胆固醇分布和 胞叶传单； 2）检查SPM中的胆固醇外侧结构域； 3） SPM外生和胞质小叶中的磷脂分布； 4） 鞘磷脂参与胆固醇结构域调节； 5） 脑固醇载体蛋白和胆固醇结构域的调节；和 6）胆固醇结构域和突触前钙。这是我们的工作 假设衰老会损害膜调节的能力 胆固醇结构域以及胆固醇结构域的这种变化修饰 神经元钙。

项目成果

Recent advances in brain cholesterol dynamics: transport, domains, and Alzheimer's disease.

脑胆固醇动力学的最新进展：运输、域和阿尔茨海默病。

• DOI: 10.1007/s11745-999-0357-9
• 发表时间: 1999
• 期刊: Lipids
• 影响因子: 1.9
• 作者: Wood,WG;Schroeder,F;Avdulov,NA;Chochina,SV;Igbavboa,U
• 通讯作者: Igbavboa,U

Cholesterol oxidation reduces Ca(2+)+MG (2+)-ATPase activity, interdigitation, and increases fluidity of brain synaptic plasma membranes.

胆固醇氧化可降低 Ca(2 ) MG (2 )-ATPase 活性、交叉，并增加脑突触质膜的流动性。

• DOI: 10.1016/0006-8993(95)00347-s
• 发表时间: 1995
• 期刊: Brain research
• 影响因子: 2.9
• 作者: Wood,WG;Igbavboa,U;Rao,AM;Schroeder,F;Avdulov,NA
• 通讯作者: Avdulov,NA

Age differences in the expression of metabotropic glutamate receptor 1 and inositol 1,4,5-trisphosphate receptor in mouse cerebellum.

小鼠小脑代谢型谷氨酸受体1和肌醇1,4,5-三磷酸受体表达的年龄差异。

• DOI: 10.1016/s0304-3940(98)00127-x
• 发表时间: 1998
• 期刊: Neuroscience letters
• 影响因子: 2.5
• 作者: Simonyi,A;Xia,J;Igbavboa,U;Wood,WG;Sun,GY
• 通讯作者: Sun,GY

Brain membrane cholesterol domains, aging and amyloid beta-peptides.

脑膜胆固醇结构域、衰老和淀粉样β-肽。

• DOI: 10.1016/s0197-4580(02)00018-0
• 发表时间: 2002
• 期刊: Neurobiology of aging
• 影响因子: 4.2
• 作者: Wood,WGibson;Schroeder,Friedhelm;Igbavboa,Urule;Avdulov,NicolaiA;Chochina,SvetlanaV
• 通讯作者: Chochina,SvetlanaV

Bacillus cereus DNA topoisomerase I and IIIalpha: purification, characterization and complementation of Escherichia coli TopoIII activity.

• DOI: 10.1093/nar/gki846
• 发表时间: 2005
• 期刊: NUCLEIC ACIDS RESEARCH
• 影响因子: 14.9
• 作者: Li, ZY;Hiasa, H;DiGate, R
• 通讯作者: DiGate, R