SCF in liver repair after hepatectomy or toxic injury

描述（由申请人提供）衰竭的肝脏是唯一一个我们没有药物或机械支持的重要器官。肝脏也是独特的，因为它可以再生一个正常的功能细胞团，以应对许多损伤，而不是大多数器官修复自己与非功能性疤痕。肝衰竭是一个重要的临床问题，发生在各种毒性，创伤性和感染性损伤后。肝肿瘤切除术后偶尔也会出现肝功能衰竭。更重要的是，当治愈性切除将留下不足量的功能性肝组织时，通常排除肝切除，最终导致患者死亡。在美国，意外和有目的的对乙酰氨基酚过量占急性肝功能衰竭病例的20%。对乙酰氨基酚中毒会导致直接的肝细胞损伤，患者的生存在很大程度上取决于肝脏从损伤中恢复和再生的能力。对乙酰氨基酚诱导的肝损伤的特点，但是，肝脏保护，修复和再生的机制尚未得到充分的研究。该提案检查了一种特定的细胞因子，干细胞因子（SCF），在对乙酰氨基酚诱导的肝毒性过程中以及70%肝切除术后的肝细胞保护和再生。SCF是一种重要的白细胞造血因子，参与多种白细胞亚群尤其是肥大细胞的增殖和成熟。最近，它已被证明是正常结构细胞（如肝细胞）发育的重要因素。我们将利用两种小鼠模型，对乙酰氨基酚中毒和70%肝切除术，研究SCF在肝损伤后的作用。我们推测SCF通过两种机制发挥作用，具有抗凋亡保护作用，以及增强肝细胞再生反应。为了验证这一假设，我们将重点关注SCF相关肝脏修复的机制，利用以下特定目标：1）检查70%肝切除术或对乙酰氨基酚诱导的损伤后肝SCF的表达、产生和细胞来源，2）检查在毒性或创伤性肝损伤的情况下跨膜SCF与可溶性SCF及其受体c-kit的调节，3）探讨SCF对中毒性肝损伤后肝细胞凋亡和增殖的影响及其作用机制; 4）探讨SCF与IL-6在中毒性肝损伤后肝细胞恢复中的相互作用。这些研究将有助于阐明SCF介导的肝细胞保护和再生在临床相关的肝切除和毒性模型的新机制。

DESCRIPTION (provided by applicant)The failing liver is the only vital organ for which we have no means of pharmacologic or mechanical support. The liver is also unique in that it can regenerate a normal functional cellular mass in response to many injuries, as opposed to most organs which repair themselves with non-functional scar. Liver failure is an important clinical problem that occurs after a variety of toxic, traumatic, and infectious insults. Liver failure also occasionally follows major hepatic resections for tumor. More importantly, hepatic resection is often precluded when a curative resection will leave an inadequate amount of functioning hepatic tissue, ultimately resulting in the death of the patient. Accidental and purposeful acetaminophen overdose accounts for 20 percent of acute liver failure cases in the U.S. Acetaminophen poisoning causes direct hepatocyte damage and patient survival relies heavily upon the liver's ability to recover from the damage and regenerate. Acetaminophen-induced liver injury is well characterized, however, the mechanisms of liver protection, repair, and regeneration have not been fully examined. This proposal examines a specific cytokine, stem cell factor (SCF), in hepatocyte protection and regeneration during acetaminophen-induced liver toxicity, as well as following 70 percent hepatectomy. SCF is well-known as an important leukocyte hematopoietic factor, involved in the proliferation and maturation of multiple leukocyte subsets, especially mast cells. More recently, it has been shown to be an important factor in the development of normal structural cells, such as hepatocytes. We will utilize two murine models, acetaminophen poisoning and 70 percent hepatectomy, to investigate SCF's effects following liver injury. We hypothesize that SCF functions via two mechanisms, having anti-apoptotic protective effects, as well as enhancing the hepatocyte regenerative response. To test this postulate, we will focus on mechanisms of SCF-associated liver repair utilizing the following specific aims: 1) To examine the expression, production, and cellular source of hepatic SCF following 70 percent hepatectomy or acetaminophen-induced injury, 2) To examine the regulation of transmembrane versus soluble SCF and its receptor, c-kit, in the setting of toxic or traumatic hepatic injury, 3) To investigate SCF's effects and mechanism(s) of action on hepatocyte apoptosis and proliferation after toxic or traumatic hepatic injury, and 4) To investigate the interactions of SCF and IL-6 in the liver's recovery from toxic or traumatic injury. These studies will help to elucidate novel mechanisms in SCF-mediated hepatocyte protection and regeneration in a clinically relevant liver resection and toxicity model.