ALIMENTARY TRACT LIPIDS IN HEALTH AND DISEASE

胆汁的形成和分泌控制着体内清除胆固醇和四吡咯分子的动态平衡机制，以及饮食脂肪的吸收。胆汁功能障碍会导致几种常见疾病，包括胆结石和胆汁淤积症。这一建议利用生物物理原理和物理化学方法论，进一步从分子上了解胆汁的物理、生化、形成、分泌和功能。PI和他的同事将设计和研究合适的模型系统，并将结果与与自然系统的功能和功能障碍有关的病理生理现象联系起来。他们将使用新的氟胆固醇方法学、低温电子显微镜和电子能量损失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上的相互作用，iii)确定胆汁分泌衰竭中脂蛋白X的物理化学来源和病理生理，iv)利用分析超滤法和分光光度技术确定磷脂酰胆碱、胆固醇和钙如何影响模型(双月桂酸胆红素)和天然胆红素的物理化学状态，5)利用电位滴定和溶解测定未结合胆红素在模型鼠中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；6)发现患有黑色胆结石的人是否存在回肠胆汁酸转运蛋白基因的功能异常突变。这些目标旨在促进我们对胆汁物理化学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的理解。这项系统工程应该为预防胆汁淤积症中的色素和胆固醇结石疾病以及脂质转运异常带来新的目标和策略。

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.