REGULATORY MECHANISMS IN HEPATIC METABOLISM

说明（改编自申请人的摘要）：内皮素是一种21个氨基 血管内皮细胞合成的三种酸性肽 暴露于各种压力或伤害。 所有主要器官，包括 肺、肾、心脏、脑和肝都能产生 在自分泌和旁分泌中对内皮素的激动剂效应作出反应 信号机制。 肝脏是最敏感的组织之一 在低nM时表现出血液动力学和糖原分解反应 浓度和特定的信号转导反应， pM浓度的肝源性细胞。 建议的目标 研究计划是描述监管机制， 内皮素参与哺乳动物肝脏的生理和 病理生理状况。 具体的实验目标包括： 内皮素介导的信号传导机制或反应的表征 肝源性培养细胞;特别是，内皮素受体 将鉴定和表征窦状隙内皮细胞， 内皮素介导的脂质和肽第二信使的合成将 表征; B）研究肝窦的能力 内皮细胞合成内皮素及其相关因子的研究 和调节内皮素合成的条件; c）表征 内皮素介导的信号传导机制在各种 全身和肝损伤的病理生理学模型，例如内毒素 休克、肝缺血/再灌注损伤和梗阻性黄疸。 拟议研究的成功结果将提供机制 深入了解可能是最有效的 血管活性介质尚未发现的肝脏反应， 炎症/损伤。 了解生物化学或分子的细节 内皮素受体介导的信号传导机制和代谢 在病理生理事件中对内皮素有反应的功能 可能有助于开发适当的治疗干预措施 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损伤。

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.