HSPG Interactions in Liver Disease

HSPG 在肝病中的相互作用

基本信息

批准号：
10595653
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
项目类别：
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/10595653
关键词：
Accidents 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 Immobilization Impairment Inflammation Inflammatory Injury Innate Immune Response Liver Liver Failure Liver diseases Matrilysin Mediating Molecular Molecular Conformation Mus N-acetyl-4-benzoquinoneimine Necrosis Organism Outcome Overdose Pathogenesis Pathway interactions Patient Admission Peptide Hydrolases Phenotype Predisposition Process Proliferating Recovery Resolution Role Signal Transduction Structure Sulfate Testing Therapeutic Tissues Toxic effect Treatment Efficacy Western World Wild Type Mouse acetaminophen overdose acetaminophen-induced liver injury antimicrobial peptide 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 prevent programs regenerative repaired response response to injury syndecan tissue injury tissue repair

Accidents 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 Immobilization Impairment Inflammation Inflammatory Injury Innate Immune Response Liver Liver Failure Liver diseases Matrilysin Mediating Molecular Molecular Conformation Mus N-acetyl-4-benzoquinoneimine Necrosis Organism Outcome Overdose Pathogenesis Pathway interactions Patient Admission Peptide Hydrolases Phenotype Predisposition Process Proliferating Recovery Resolution Role Signal Transduction Structure Sulfate Testing Therapeutic Tissues Toxic effect Treatment Efficacy Western World Wild Type Mouse acetaminophen overdose acetaminophen-induced liver injury antimicrobial peptide 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 prevent programs regenerative repaired response response to injury syndecan tissue injury tissue repair

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项目摘要

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提案的核心目标是了解乙酰肝素的分子和细胞相互作用硫酸盐蛋白聚糖（HSPGS）调节对乙酰氨基酚（APAP）诱导的肝损伤的发病机理（aili）。意外或故意滥用APAP是西方世界急性肝衰竭的主要原因。虽然触发艾利的机制是众所周知的，但促进肝脏恢复的机制知之甚少。 HSPG通过其乙par硫酸盐（HS）链结合并调节各种组织损伤因素，但 HSPG在组织损伤和体内修复中的显着性和机制在很大程度上尚不清楚。我们研究了aili中主要细胞表面HSPG的Syndecan-1（SDC1）（SDC1）的作用。删除SDC1 在小鼠中导致APAP肝病中肝损伤的进展。但是，直接APAP肝毒性在APAP过量后，SDC1缺失不影响APAP过量后的早期，这表明SDC1稍后调节影响APAP肝病进展和结果的机制。旺盛的aili表型 SDC1 NULL（SDC1 - / - ）小鼠被追溯到肝脏中夸张的先天免疫反应和缺乏症在肝细胞和肝细胞增殖中的蛋白生存AKT信号传导中，这导致了肝脏的扩增损害。给予纯化的SDC1或乙酰肝素化合物，其中包含2-O-硫酸盐图案拯救了SDC1 - / - 通过抑制先天免疫反应，通过增强肝细胞增殖和肝脏来抑制AILI的小鼠维修。此外，与N-乙酰半胱氨酸相比，HS显示出明显延长的治疗功效（NAC），APAP过量的临床解毒剂。这些发现表明SDC1和HS，无论是单独还是在与NAC结合使用，可以提供一种对抗AILI的新治疗策略，尤其是在治疗患者时 NAC治疗后被录取不再有效。基于这些初步数据，我们建议SDC1是关键的内源性因素，阻止肝损伤的延续并促进艾利的肝脏修复。这假设将以3个特定目的进行检验。 AIM 1将定义如何从肝细胞中释放出SDC1。 AILI并确定SDC1 HS中的离散结构基序可对AILI提供保护。 AIM 2意志阐明了SDC1如何停止AILI的生物学机制。 AIM 3将确定SDC1如何增强肝细胞增殖并促进艾利的肝脏修复。这些研究有望建立肝损伤和修复中的新综合途径。