Receptor Guanylyl Cyclases in Regenerating Liver

描述（由申请人提供）：我们的长期目标是了解控制肝脏生长、分化和再生的机制。本研究的重点是肝脏生长和功能受受体胍基环化酶调节的机制，受体胍基环化酶是连接细胞外信号和生成环GMP （cGMP）的分子，cGMP是一种关键的细胞内信号分子。在其他已知的作用中，cGMP与调节程序性细胞死亡或细胞凋亡的机制密切相关。在肝损伤或细胞损失的数小时内，胍基环化酶C（一种cgmp形成受体胍基环化酶）急剧上调。GC-C由观音蛋白和尿观音蛋白激活。在再生过程中，肝脏暴露于许多激素和生长因子，最显著的是tnf - α，这是已知的细胞凋亡诱导剂。该建议的中心假设是，配体介导的受体胍基环化酶活化保护再生肝细胞和非实质细胞免受再生反应中各种细胞因子的致命作用。胍基环化酶也可能对抑制肝细胞增殖以达到正常的肝脏质量和防止肿瘤发生至关重要。我们的目标是确定：1)GC-A或GC-C基因靶向小鼠在三种不同刺激下的肝脏再生是如何改变的；2)颗粒基环化酶活化对细胞凋亡和增殖的影响；3)膜观酰基环化酶如何改变培养肝细胞和再生肝细胞凋亡信号机制。这些目标的进展将提高我们对肝脏如何在肝脏生长和再生的戏剧性恢复过程中抑制程序性细胞死亡的理解。肝脏再生是正常和改变生长调节的其他条件的范例，包括组织肥大、伤口愈合和癌症。除了阐明肝脏生长控制的机制外，我们的研究可能最终有助于开发方法来减少移植过程中病毒或毒性损伤后的肝细胞死亡，以及移植和生物人工肝的前体细胞分化。

DESCRIPTION (provided by applicant): Our long-term goal is to understand the mechanisms that control the growth, differentiation, and regeneration of the liver. This study focuses on the mechanisms by which liver growth and function is regulated by receptor guanylyl cyclases, molecules that link extracellular signals to the generation of cyclic GMP (cGMP), a critical intracellular signaling molecule. Among other known actions, cGMP is strongly linked to mechanisms regulating programmed cell death, or apoptosis. Within hours of liver damage or cellular loss, there is a dramatic upregulation of guanylyl cyclase C, a cGMP-forming receptor guanylyl cyclase. GC-C is activated by the proteins guanylin and uroguanylin. During regeneration, the liver is exposed to a number of hormones and growth factors, most notably TNF-alpha, which are known inducers of apoptosis. The central hypothesis of this proposal is that ligand-mediated activation of the receptor guanylyl cyclases protects regenerating hepatocytes and non-parenchymal cells from the lethal actions of the various cytokines involved in the regenerative response. The guanylyl cyclases may also be critical to restraining hepatocyte proliferation to achieve normal liver mass and to prevent neoplasia. We aim to determine: 1) how liver regeneration in response to three different stimuli is altered in GC-A or GC-C gene-targeted mice; 2) the consequences of particulate guanylyl cyclase activation on apoptosis and cell proliferation; and 3) how membrane guanylyl cyclases alter apoptotic signaling mechanisms in cultured hepatocytes and in regenerating liver. Progress toward these aims will improve our understanding of how the liver inhibits programmed cell death during the dramatic restoration of liver growth of regeneration. Liver regeneration is a paradigm for other conditions of normal and altered growth regulation, including tissue hypertrophy, wound healing, and cancer. In addition to elucidating mechanisms of growth control in the liver, our studies may ultimately aid in developing methods to reduce liver cell death following viral or toxic injury during transplantation and in the differentiation of precursor cells for transplantation and bio-artificial livers.