ALIMENTARY TRACT LIPIDS IN HEALTH AND DISEASE

胆汁的形成和分泌控制着机体消除胆固醇和四吡咯分子的稳态机制，以及膳食脂肪的吸收。胆汁功能障碍可引起几种常见疾病，包括胆结石和胆汁淤积。本文采用生物物理原理和物理化学方法，进一步了解胆汁的物理生化、形成、分泌和功能。PI及其同事将设计和研究适当的模型系统，并将结果与与天然系统功能和功能障碍有关的病理生理现象联系起来。他们将使用I)新的氟胆固醇方法，低温电子显微镜和电子能量损失光谱来阐明胆固醇分子从血液转移到肝细胞和胆汁的物理化学途径，ii)表征胶束溶液中胆盐分子与鞘磷脂的相互作用，以及与胆固醇分泌，吸收和凋亡相关的界面。iii)确定脂蛋白X在胆汁分泌衰竭中的物理化学来源和病理生理学，iv)定义磷脂酰胆碱、胆固醇和钙如何影响模型（双胍胆红素）和天然胆汁中天然共轭胆红素的物理化学状态，采用分析性超离心和分光光度法技术；V)利用电位滴定法和溶出法测量模型胆汁中非共轭胆红素的亚稳态和平衡溶解度，并将这些信息与色素结石的病理生理联系起来；vi)发现~黑~色素胆结石患者是否存在回肠胆汁酸转运体基因的功能失调突变。这些目标旨在提高我们对胆汁物理化学的理解，以及胆固醇和胆红素进出肝脏和消化道的正常和异常运动。该系统项目将为预防色素和胆固醇结石疾病以及胆汁淤积中的脂质转运异常提供新的目标和策略。

Bile formation and secretion control homeostatic mechanisms for eliminating cholesterol and tetrapyrrole molecules form the organism as well as absorption of dietary fat. Bile dysfunction causes several common diseases, including gallstones and cholestasis. This proposal employs biophysical rationale and physical-chemical methodology to further molecular understanding of the physical biochemistry of bile, its formation, secretion and functions. The PI and colleagues will design and study appropriate model systems and correlate the results with pathophysiological phenomena pertaining to the function and dysfunction of native systems. They will use I)novel flurocholesterol methodology, cryoelectron microscopy and electron energy-loss spectroscopy to elucidate physical-chemical pathways whereby cholesterol molecules are transferred from blood to liver cell and bile, ii) characterize interactions of bile salt molecules with sphingomyelin in micellar solutions and at interfaces related to cholesterol secretion, absorption and apoptosis, iii) determine the physical-chemical origin and pathophysiology of lipoprotein X in bile secretory failure, iv) define how phosphatidylcholine, cholesterol and calcium influence the physical- chemical state of natural conjugated bilrubins in model (bilrubin ditaurate) and native biles employing analytical ultracentrifugation and spectrophotometric techniques, v) measure the metastable and equilibrium solubilities of unconjugated bilirubin in modelbiles utilizing potentiometric titration and dissolution and correlate the information pathophysiologically with pigment-stone biles, vi) discover whether humans with ~black~ pigment gallstones have dysfunctional mutations of the ileal bile acid transporter gene. These objectives are designed to advance our understanding of physical chemistry of bile as ell as normal and abnormal movements of cholesterol and billirubin to and from the liver and alimentary tract. The systematic project should lead to new targets and strategies for prevention of pigment and cholesterol gallstone diseases as well as lipid transport abnormalities sin cholestasis.