REGULATORY MECHANISMS IN HEPATIC METABOLISM

描述(摘自申请者的摘要)：内皮素是一个21个氨基酸 血管内皮细胞合成三种异肽的酸性多肽 暴露在各种类型的压力或伤害之下。所有主要器官，包括 肺、肾、心、脑和肝都被证明能产生和 内皮素对自分泌和旁分泌的兴奋作用 信令机制。肝脏是反应最灵敏的组织之一 在低NM时同时表现出血流动力学和糖原分解反应 培养细胞的浓度和特异性信号转导反应 PM浓度下的肝来源细胞。建议的目标是 研究计划是描述监管机制的特征，其中 内皮素参与哺乳动物肝脏的生理和生理功能 病理生理状况。具体的实验目标包括：a) 内皮素介导的信号转导机制或反应的特征 肝来源的培养细胞；具体地说，内皮素受体 将对正弦内皮细胞进行鉴定和表征 内皮素介导的脂质和多肽二级信使的合成 B)肝窦形成能力的研究 内皮细胞合成内皮素及其影响因素的研究进展 和调节内皮素合成的条件；c)表征 内皮素介导的信号转导机制在不同环境中的作用 内毒素等全身和肝脏损伤的病理生理模型 休克、肝脏缺血/再灌流损伤和梗阻性黄疸。 拟议研究的成功结果将提供机械性的 洞察可能是最强大的 肝脏对血管活性物质的反应尚未发现 炎症/损伤。了解生物化学或分子细节 内皮素受体介导的信号转导机制与代谢 内皮素在病理生理过程中的反应功能 可以促进适当的治疗干预措施的发展 旨在最大限度地减少或改善以下肝功能损害 暴露于全身性或特定的肝脏创伤。

DESCRIPTION (Adapted from applicant's abstract): Endothelin is a 21 amino acid peptide synthesized as three isopeptides by vascular endothelial cells exposed to various types of stress or injury. All major organs including lung, kidney heart, brain and liver have been shown to both produce and respond to the agonist effects of endothelin in autocrine and paracrine signaling mechanisms. The liver is one of the most responsive tissues exhibiting both hemodynamic and glycogenolytic responses at low nM concentrations and specific signal transduction responses in cultured hepatic-derived cells at pM concentrations. The objective of the proposed research program is to characterize regulatory mechanisms in which endothelin participates in the mammalian liver in physiological and pathophysiological situations. Specific experimental goals include: a) characterization of endothelin-mediated signaling mechanisms or responses in hepatic-derived cultured cells; specifically, endothelin receptors on sinusoidal endothelial cells will be identified and characterized and endothelin-mediated synthesis of lipid and peptide secondary messengers will be characterized; b) investigation of the capability of hepatic sinusoidal endothelial cells to synthesize endothelin and the elucidation of factors and conditions which regulate endothelin synthesis; c) characterization of endothelin-mediated signaling mechanism operative in various pathophysiological models of systemic and hepatic injury such as endotoxic shock, hepatic ischemia/reperfusion injury, and obstructive jaundice. Successful outcomes from the proposed research will provide mechanistic insight into the role and the importance of probably the most potent vasoactive mediator yet discovered in the hepatic responses to inflammation/injury. Understanding the biochemical or molecular details of the endothelin receptor-mediated signaling mechanisms and the metabolic functions which are responsive to endothelin in pathophysiological episodes may facilitate the development of appropriate therapeutic interventions designed to minimize or ameliorate impairment of hepatic function following exposure to systemic or specific hepatic trauma.