ALIMENTARY TRACT LIPIDS IN HEALTH AND DISEASE

胆汁的形成和分泌控制体内平衡机制，以消除胆固醇和四吡咯分子形成的生物体以及吸收的膳食脂肪。 胆汁功能障碍导致几种常见疾病，包括胆结石和胆汁淤积。 该建议采用生物物理学原理和物理化学方法，以进一步从分子水平了解胆汁的物理生物化学、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，并将结果与有关天然系统功能和功能障碍的病理生理学现象相关联。 他们将使用I）新型氟胆固醇方法，冷冻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）表征胆盐分子与鞘磷脂在胶束溶液中以及在与胆固醇分泌，吸收和凋亡相关的界面处的相互作用，iii）确定胆汁分泌衰竭中脂蛋白X的物理化学起源和病理生理学，iv）定义磷脂酰胆碱，胆固醇和钙影响模型中天然结合胆红素的理化状态（胆红素二月桂酸酯）和天然胆汁，v）利用电位滴定和溶解测量非结合胆红素在模型胆汁中的亚稳态和平衡溶解度，并将该信息与色素结石胆汁病理生理学相关，vi）发现患有黑色素胆结石的人是否存在回肠胆汁酸转运蛋白基因的功能性突变。这些目标旨在促进我们对胆汁的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。 这一系统工程将为胆色素结石和胆固醇结石以及胆汁淤积中脂质转运异常的预防提供新的靶点和策略。

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.