Receptor Guanylyl Cyclases in Regenerating Liver

描述(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。这项研究的重点是受体鸟苷酰环酶调节肝脏生长和功能的机制，该酶是将细胞外信号与细胞内关键信号分子环GMP(CGMP)的产生联系起来的分子。在其他已知的作用中，cGMP与调节细胞程序性死亡或凋亡的机制密切相关。在肝损伤或细胞丢失的几个小时内，鸟苷酸环化酶C显著上调，这是一种形成cGMP的受体鸟苷酸环化酶。GC-C由鸟苷和尿鸟苷两种蛋白质激活。在再生过程中，肝脏暴露在一系列激素和生长因子中，其中最著名的是肿瘤坏死因子-α，它们是已知的诱导细胞凋亡的因素。这一建议的中心假设是，配体介导的受体鸟苷酸环化酶的激活保护再生肝细胞和非实质细胞免受参与再生反应的各种细胞因子的致死作用。鸟苷酸环化酶在抑制肝细胞增殖、达到正常肝质量和防止肿瘤形成方面也可能起着关键作用。我们的目标是确定：1)在GC-A或GC-C基因靶向的小鼠中，响应三种不同刺激的肝再生是如何改变的；2)颗粒鸟苷酸环化酶激活对细胞凋亡和细胞增殖的影响；以及3)膜鸟苷酸环化酶如何改变培养的肝细胞和再生肝中的凋亡信号机制。朝着这些目标的进展将提高我们对肝脏如何在显著恢复肝脏再生生长的过程中抑制程序性细胞死亡的理解。肝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减少移植过程中病毒或毒性损伤后肝细胞死亡的方法，以及移植和生物人工肝的前体细胞的分化。

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.