Regulation of hepatic repair responses by metabolites of the uric acid pathway

描述（由申请方提供）：肝细胞凋亡导致修复反应，包括肝星状细胞（HSC）趋化性、收缩和基质重塑。来自凋亡肝细胞的调节这些反应的信号很少被识别。尿酸途径（UAP）介导嘌呤分解为尿酸。通过该途径的通量在组织中大大增加，通过坏死或凋亡进行细胞死亡，并且UAP代谢物调节许多器官中对损伤的细胞反应。我们表明，在原代小鼠HSC中，腺苷i）导致抑制PDGF诱导的HSC中的Ca++动员和趋化性，ii）通过A2a受体诱导HSC的肌动蛋白重组和收缩，iii）上调TGF β和胶原1 mRNA。包括尿酸在内的许多其他UAP代谢物也诱导HSC收缩，此外还上调TGF β和胶原1 mRNA。在两种肝损伤模型中，远端抑制UAP导致更严重的纤维化。该建议的假设是，UAP的代谢产物调节HSC分化以响应肝脏中的组织损伤。具体目标1：a）确定负责腺苷介导的肌动蛋白重组和HSC收缩的细胞内信号传导途径B）确定cAMP、PKA途径在腺苷介导的抑制PDGF诱导的细胞溶质Ca++增加中的作用。具体目标二：a）确定腺苷下游的UAP代谢物是否抑制ATP和PDGF介导的Ca++动员和原代HSC的趋化性B）确定腺苷下游的UAP代谢物（尿酸除外）的作用中对腺苷受体的需求c）确定负责尿酸诱导的HSC分化的细胞内信号传导途径。具体目的3：a）确定免疫系统在腺苷介导的体内肝纤维化调节中的作用。B）测定腺苷调节缺血性肝脏中肝内血管阻力的能力。我们已经确定了一个新的作用，为UAP在HSC的分化和调节。这确定了一组在肝修复中起作用的新分子，并对肝纤维化的新疗法产生了影响。

DESCRIPTION (provided by applicant): Hepatocyte apoptosis results in repair responses including hepatic stellate cell (HSC) chemotaxis, contraction and matrix remodeling. The signals from apoptotic hepatocytes which modulate these responses are poorly identified. The uric acid pathway (UAP) mediates the breakdown of purines to uric acid. Flux through this pathway is greatly increased in tissues .undergoing cellular death by necrosis or apoptosis, and UAP metabolites regulate cellular responses to injury in many organs. We show that in primary mouse HSC adenosine i) results in inhibition of PDGF induced Ca++ mobilization and chemotaxis in HSC ii) induces actin reorganization and contraction of HSC via the A2a receptor iii) upregulates TGF beta and collagen 1 mRNA. A number of other UAP metabolites including uric acid also induce HSC contraction, and in addition upregulate TGF beta and collagen 1 mRNA. Distal inhibition of the UAP results in greater fibrosis in two models of liver injury. The hypothesis for this proposal is that metabolites of the UAP regulate HSC differentiation in response to tissue injury in the liver. Specific Aim 1: a) Determine the intracellular signaling pathways responsible for adenosine mediated actin reorganization and HSC contraction b) Determine the role of the cAMP, PKA pathway in adenosine mediated inhibition of PDGF induced cytosolic Ca++ increase. Specific Aim 2: a) Determine if UAP metabolites downstream of adenosine inhibit ATP and PDGF mediated Ca++ mobilization and chemotaxis of primary HSC b) Establish the requirement for adenosine receptors in the effect of UAP metabolites downstream of adenosine with the exception of uric acid c) Determine the intracellular signaling pathways responsible for uric acid induced HSC differentiation. Specific Aim 3: a) Determine the role of the immune system in adenosine mediated regulation of liver fibrosis in-vivo. b) Determine the ability of adenosine to regulate intrahepatic vascular resistance in cirrhotic livers. We have identified a new role for the UAP in HSC differentiation and regulation. This identifies a new set of molecules with a role in hepatic repair, and has implications for new therapies in liver fibrosis.