ALIMENTARY TRACT LIPIDS IN HEALTH AND DISEASE

消化道脂质与健康和疾病的关系

• 批准号: 2684155
• 负责人: MARTIN CONRAD CAREY
• 金额: $ 50.15万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1985
• 资助国家: 美国
• 起止时间: 1985-07-01 至 1999-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2684155
• 关键词: bile; bilirubin; blood lipoprotein; blood lipoprotein metabolism; cholanate compound; cholelithiasis; cholesterol; crystallization; electron probe spectrometry; fluorescence spectrometry; gastrointestinal absorption /transport; guinea pigs; human subject; hyperbilirubinemia; hypercholesterolemia; isomer; laboratory mouse; lipid metabolism; lipid transport; liver metabolism; nuclear magnetic resonance spectroscopy; pharmacokinetics; phosphatidylcholines; physical chemical interaction; steroid metabolism; transport proteins

The overall research plan applies physical-chemical rationale as well as biochemical and biophysical techniques to define the pathophysiology of biologically important alimentary tract lipids and lipid-protein systems. As phase behavior, fine structures and properties of model systems are elucidated, this information is correlated with actual pathophysiological phenomena. The overall goals aim at understanding how the delicate physical-chemical balance of lipids and lipid-protein systems in multicomponent lipid-rich tissues is perturbed hepatobiliary diseases so that strategies for their prevention and treatment can be developed. In studies of normal and abnormal bile formation, fluorescence spectroscopy will be used to define putative roles of hepatic phosphatidylcholine transfer protein in combination with sterol carrier protein-2 and submicellar bile salts in promoting cytosolic transport of biliary lecithins. 13C nuclear magnetic resonance spectroscopy will be applied to detection of canalicular membrane translocators ("flippases") and defining their roles in lecithin and cholesterol secretion into bile. With hepatocyte couplets, the physical-chemical state and phase transitions of canalicular bile will be defined using the complementary approaches of microscope quasielastic light scattering spectroscopy and electron spectroscopic imaging. The origin and fate of plasma lipoprotein X, an abnormal lipoprotein causing hypercholesterolemia in cholestasis, will be studied. The hypothesis that lipoprotein X is a misdirected "nascent" biliary vesicle will be explored by showing that biliary lipid "flippases" and anion transporters are misplaced in basolateral membranes during cholestasis but are correctly inserted into canalicular membranes following ursodeoxycholic acid therapy. The physical-chemical state of bile and gallstone formation will be studied by combining physical- chemical, ultrastructural, and pathophysiological approaches with particular reference to critical nuclei and vesicle fusion in mucin gel. Cholesterol nucleation, crystallization and growth from bile will be investigated employing model bile systems as well as biles from humans and inbred mice where the lithogenic genes are being defined. Altered hydrophilic-hydrophobic balance of biliary proteins as a secondary response to lithogenic bile will be investigated by hydrophobic interaction chromatography and the effects of purified human as well as prairie-dog biliary proteins on the nucleation maps from model systems will be tested. Phase equilibria and micellar properties of the muricholate epimers, biomedically-relevant hydrophilic bile salts resistant to bacterial catabolism, will be investigated to establish molecular mechanisms required for inhibiting crystalline phase transitions in human bile. Elucidation of unconjugated bilirubin absorption from the colon and its enterohepatic cycling in ileal dysfunction induced by chemical and dietary means will be investigated using the intact rat; the pathophysiologic paradigm developed should serve as a model for investigating the etiology of non-hemolytic pigment gallstone formation in humans.

总体研究计划应用物理化学原理以及 生物化学和生物物理技术来定义病理生理学 具有生物学重要意义的消化道脂质和脂质-蛋白质系统。 作为相行为，模型系统的精细结构和性质是 阐明，该信息与实际的病理生理学相关 现象。总体目标旨在了解微妙的 脂质和脂质-蛋白质系统的物理化学平衡 多成分富含脂质的组织会干扰肝胆疾病，因此 可以制定预防和治疗策略。在 正常和异常胆汁形成、荧光光谱的研究 将用于定义肝磷脂酰胆碱的假定作用 转移蛋白与甾醇载体蛋白-2 组合， 亚胶束胆盐促进胆汁的胞质转运 卵磷脂。 13C核磁共振波谱将应用于 检测小管膜易位蛋白（“翻转酶”）并定义 它们在卵磷脂和胆固醇分泌到胆汁中的作用。和 肝细胞对、物理化学状态和相变 小管胆汁将使用以下补充方法进行定义 显微镜准弹性光散射光谱和电子 光谱成像。血浆脂蛋白X的起源和命运 异常脂蛋白导致胆汁淤积中的高胆固醇血症， 研究过。脂蛋白 X 是一个被误导的“新生”假设 将通过显示胆汁脂质“翻转酶”来探索胆囊 阴离子转运蛋白在基底外侧膜中错位 胆汁淤积但正确插入小管膜 熊去氧胆酸治疗后。物理化学状态 将通过结合物理方法来研究胆汁和胆结石的形成 化学、超微结构和病理生理学方法 特别参考粘蛋白凝胶中的关键核和囊泡融合。 胆汁中的胆固醇成核、结晶和生长将 研究使用模型胆汁系统以及来自人类的胆汁和 正在定义成石基因的近交小鼠。改变 胆汁蛋白质的亲水-疏水平衡作为次要因素 将通过疏水性研究对成石胆汁的反应 相互作用色谱法和纯化的人的影响以及 模型系统成核图上的草原土拨鼠胆汁蛋白 将受到测试。 相平衡和胶束特性 muricholate差向异构体，生物医学相关的亲水性胆汁盐 抵抗细菌分解代谢，将进行研究以确定 抑制结晶相变所需的分子机制 在人类胆汁中。阐明非结合胆红素的吸收 结肠及其肠肝循环在回肠功能障碍中的作用 将使用完整的大鼠来研究化学和饮食方法；这 所开发的病理生理学范式应作为模型 探讨非溶血性胆色素结石形成的病因 人类。