HSPG Interactions in Liver Disease

HSPG 在肝病中的相互作用

• 批准号: 10446447
• 负责人: Pyong Woo Park
• 金额: $ 45.11万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10446447
• 关键词: Acetaminophen; Acetylcysteine; Acute Disease; Acute Liver Failure; Affect; Analgesics; Antidotes; Binding; Biological; Blood Coagulation Factor; Cell Proliferation; Cell physiology; Cell surface; Cessation of life; Chemotactic Factors; Chronic Disease; Cicatrix; Clinical; Complex; Data; Destinations; Disease Progression; Dose; Drops; Endogenous Factors; Etiology; Extracellular Matrix; Generations; Genetic; Goals; Growth Factor; HMGB1 gene; Hemostatic function; Heparan Sulfate Proteoglycan; Heparitin Sulfate; Hepatocyte; Hepatotoxicity; Imines; Immobilization; Impairment; Inflammation; Inflammatory; Injury; Innate Immune Response; Lead; Liver; Liver Failure; Liver diseases; Matrilysin; Mediating; Molecular; Molecular Conformation; Mus; Necrosis; Organism; Outcome; Overdose; Pathogenesis; Pathway interactions; Patients; Peptide Hydrolases; Phenotype; Process; Recovery; Resolution; Role; Signal Transduction; Structure; Sulfate; Testing; Therapeutic; Time; Tissues; Toxic effect; Treatment Efficacy; Western World; Wild Type Mouse; acetaminophen overdose; acetaminophen-induced liver injury; antimicrobial peptide; base; cell motility; combat; cytokine; drug induced liver injury; healing; in vivo; injured; injury and repair; liver cell proliferation; liver injury; liver repair; loss of function; neutrophil; novel; novel therapeutic intervention; novel therapeutics; para-benzoquinone; prevent; programs; regenerative; repaired; response; response to injury; syndecan; tissue injury; tissue repair

ABSTRACT The central goal of this R01 proposal is to understand how molecular and cellular interactions of heparan sulfate proteoglycans (HSPGs) modulate the pathogenesis of acetaminophen (APAP)-induced liver injury (AILI). Accidental or intentional misuse of APAP is the leading cause of acute liver failure in the Western world. While mechanisms that trigger AILI are well known, those that facilitate liver recovery are less understood. HSPGs bind and regulate various tissue injury factors through their heparan sulfate (HS) chains, but the significance and mechanisms of HSPGs in tissue injury and repair in vivo remain largely unknown. We examined the role of syndecan-1 (Sdc1), the major cell surface HSPG of hepatocytes, in AILI. Deletion of Sdc1 in mice led to unopposed progression of liver injury in APAP liver disease. However, direct APAP hepatoxicity at early times after APAP overdose was unaffected by Sdc1 deletion, suggesting that Sdc1 regulates later mechanisms that affect the progression and outcome of APAP liver disease. The exuberant AILI phenotypes of Sdc1 null (Sdc1-/-) mice were traced to an exaggerated innate immune response in the liver and a deficiency in pro-survival Akt signaling in hepatocytes and hepatocyte proliferation, which led to amplification of liver damage. Administration of purified Sdc1 or heparan compounds containing 2-O-sulfate motifs rescued Sdc1-/- mice from AILI by inhibiting innate immune responses, and by potentiating hepatocyte proliferation and liver repair. Furthermore, HS showed a significantly prolonged therapeutic efficacy as compared to N-acetylcysteine (NAC), the clinical antidote for APAP overdose. These findings suggest that Sdc1 and HS, either alone or in combination with NAC, could provide a new therapeutic strategy to combat AILI, especially in treating patients admitted after NAC treatment is no longer effective. Based on these preliminary data, we propose that Sdc1 is a critical endogenous factor that halts the perpetuation of liver injury and facilitates liver repair in AILI. This hypothesis will be tested in 3 specific aims. Aim 1 will define how Sdc1 is released from hepatocytes during AILI and establish that discrete structural motifs in Sdc1 HS provide protection against AILI. Aim 2 will elucidate the biological mechanisms of how Sdc1 halts the progression of AILI. Aim 3 will determine how Sdc1 enhances hepatocyte proliferation and facilitates liver repair in AILI. These studies are expected to establish a new integrated pathway in liver injury and repair.

抽象的 该 R01 提案的中心目标是了解乙酰肝素的分子和细胞相互作用如何 硫酸蛋白聚糖（HSPG）调节对乙酰氨基酚（APAP）诱导的肝损伤的发病机制 （艾力）。意外或故意滥用 APAP 是西方世界急性肝衰竭的主要原因。 虽然引发 AILI 的机制众所周知，但促进肝脏恢复的机制却鲜为人知。 HSPG 通过其硫酸乙酰肝素 (HS) 链结合并调节各种组织损伤因子，但 HSPGs 在体内组织损伤和修复中的意义和机制仍然很大程度上未知。我们 研究了肝细胞主要细胞表面 HSPG syndecan-1 (Sdc1) 在 AILI 中的作用。删除Sdc1 小鼠体内导致 APAP 肝病肝损伤的无阻碍进展。然而，APAP 的直接肝毒性 在 APAP 过量服用后的早期，Sdc1 缺失并未对其产生影响，表明 Sdc1 的调节较晚 影响 APAP 肝病进展和结果的机制。丰富的 AILI 表型 Sdc1 null (Sdc1-/-) 小鼠被追踪到肝脏中过度的先天免疫反应和缺陷 参与肝细胞中促存活 Akt 信号传导和肝细胞增殖，从而导致肝细胞扩增 损害。施用纯化的 Sdc1 或含有 2-O-硫酸基序的乙酰肝素化合物可挽救 Sdc1-/- AILI 小鼠通过抑制先天免疫反应并增强肝细胞增殖和肝脏 维修。此外，与 N-乙酰半胱氨酸相比，HS 显示出显着延长的治疗效果 (NAC)，APAP过量的临床解毒剂。这些发现表明 Sdc1 和 HS 单独或组合在一起 与 NAC 结合，可以提供一种新的治疗策略来对抗 AILI，特别是在治疗患者方面 入院后NAC治疗不再有效。根据这些初步数据，我们建议 Sdc1 是 一种关键的内源性因素，可阻止 AILI 中肝损伤的持续存在并促进肝脏修复。这 假设将在 3 个具体目标中进行检验。目标 1 将定义 Sdc1 在 AILI 并确定 Sdc1 HS 中的离散结构基序可提供针对 AILI 的保护。目标2将 阐明 Sdc1 如何阻止 AILI 进展的生物学机制。目标 3 将确定 Sdc1 如何 增强肝细胞增殖并促进 AILI 中的肝脏修复。这些研究预计将建立一个 肝损伤和修复的新整合途径。