ALIMENTARY TRACT LIPIDS IN HEALTH AND DISEASE

总体研究计划应用了物理化学原理以及 生物化学和生物物理技术用于确定脑血管疾病的病理生理学 具有重要生物学意义的消化道类脂和脂-蛋白系统。 作为相行为，模型体系的精细结构和性质是 阐明后，这些信息与实际的病理生理相关。 现象。总体目标旨在了解微妙的 人体脂类和脂蛋白系统的物理化学平衡 多组分富脂组织是扰乱肝胆疾病的原因 可以制定预防和治疗它们的战略。在……里面 胆汁正常与异常形成的荧光光谱研究 将被用来确定肝脏磷脂酰胆碱的假定作用 转运蛋白与甾醇载体蛋白-2和 胶束下胆盐促进胆汁胞浆转运的实验研究 卵磷脂。~(13)C核磁共振波谱将应用于 小管膜转运体(“Flippase”)的检测和定义 它们在卵磷脂和胆固醇分泌到胆汁中的作用。使用 肝细胞偶联、肝细胞的物理化学状态和相变 胆小管胆汁的定义将使用以下补充方法 显微镜准弹性光散射谱与电子 光谱成像。血浆脂蛋白X的起源和去向 脂蛋白异常导致高胆固醇血症的胆汁淤积症 学习。认为脂蛋白X是一种错误的“新生”的假说 胆囊泡的研究将通过显示胆汁脂类“翻转酶”来实现。 而阴离子转运体在基底膜中错位 胆汁淤积，但正确插入小管膜 在熊去氧胆酸治疗后。……的物理化学状态 胆汁和胆结石的形成将通过结合物理- 化学、超微结构和病理生理学方法 特别提到粘蛋白凝胶中的临界核和囊泡融合。 胆汁中胆固醇的成核、结晶和生长将是 使用模型胆汁系统以及来自人类和 定义致石基因的近亲繁殖小鼠。更改后的 胆汁蛋白的亲水-疏水平衡作为次要因素 对致石胆汁的反应将通过疏水来研究 相互作用层析及其对人纯品的影响 草原犬胆汁蛋白在模式体系成核图上的应用 将会受到考验。聚合物的相平衡和胶束性质 与生物医学相关的亲水胆盐 对细菌分解代谢的抵抗力，将进行调查以确定 抑制晶体相变所需的分子机制 在人类胆汁中。人血中未结合胆红素吸收的研究 大鼠回肠功能障碍的结肠及其肠肝循环 化学和饮食方法将使用完好的大鼠进行调查； 所开发的病理生理学范式应作为 非溶血性胆色素结石形成的病因学研究 人类。

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.