TGFb1 Receptor Inhibitors for Liver Fibrosis

TGFb1 受体抑制剂治疗肝纤维化

• 批准号: 7399773
• 负责人: WEIZHONG CAI
• 金额: $ 25.55万
• 依托单位: ANGION BIOMEDICA CORPORATION
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-03-15 至 2009-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7399773
• 关键词: Affect; Alcohol consumption; Animal Model; Antiviral Agents; Binding; Biological Assay; Biology; Cell Line; Cell physiology; Cells; Cessation of life; Chronic; Cicatrix; Cirrhosis; Clinical Trials; Collaborations; Coupling; Development; Disease; Drug Kinetics; Epidemic; Etiology; Event; Extrahepatic; Fibroblasts; Fibrosis; Functional disorder; Gene Expression; Genes; Goals; Grant; Guanosine Monophosphate; Hepatic Stellate Cell; Hepatitis B; Hepatitis C; Hepatitis C virus; Histology; Human; In Vitro; Incidence; Injury; Iron Overload; Kidney; Laboratories; Libraries; Ligation; Liver; Liver Cirrhosis; Liver Failure; Liver Fibrosis; Liver diseases; Measures; Messenger RNA; Modeling; Molecular; Myofibroblast; Obstruction; Organ; Patients; Pharmaceutical Chemistry; Phosphorylation; Phosphotransferases; Play; Portal Pressure; Principal Investigator; Property; Rattus; Reporter; Research; Role; Safety; Screening procedure; Series; Signal Transduction; Signaling Protein; Small Business Funding Mechanisms; Small Business Innovation Research Grant; TGF-beta type I receptor; Testing; Therapeutic; United States Food and Drug Administration; Up-Regulation; analog; bile duct; clinically relevant; cytokine; cytotoxicity; drug discovery; drug synthesis; expectation; experience; fibrogenesis; in vitro Assay; in vivo; in vivo Model; inhibitor/antagonist; kinase inhibitor; liver function; liver transplantation; medical schools; mimetics; molecular modeling; nonalcoholic steatohepatitis; pre-clinical; protein expression; receptor; response; small molecule; stellate cell

DESCRIPTION (provided by applicant): Liver fibrosis, a disease affecting tens of millions of patients worldwide, is the liver scarring response to chronic injury from viral hepatitis B or C, excessive alcohol use, iron overload or extrahepatic obstructions and can progress to liver cirrhosis, liver failure and death. In fact, deaths from complications of liver fibrosis/cirrhosis are expected to triple over the next decade as a result of the hepatitis C epidemic and the growing incidence of liver disease associated with non-alcoholic steatohepatitis. Currently available therapies, including antivirals, are largely ineffective in treating the underlying fibrosis, and in the majority of cases, liver transplantation is the only effective cure. Liver fibrosis, irrespective of its etiology, reflects the same cellular and molecular pathophysiology. Activation of hepatic stellate cells and conversion to myofibroblasts is the dominant event in fibrogenesis, and proceeds along a continuum that involves progressive changes in cellular function. The cytokine TGF?1 plays a central role in stellate cell activation and fibrosis. TGF?1 binds to and activates its receptor (ALK5), which phosphorylates and activates signaling proteins including Smad2, resulting in expression of upregulation of fibrotic marker genes, such as ?SMA. Our long-term goal is the development of small molecule inhibitors of the TGF?1 receptor as potential therapeutics for fibrotic liver disease. The objective of this application is to identify such inhibitors and evaluate them in two clinically relevant animal models of liver fibrosis. Small molecule inhibitors of the TGF?1 receptor are potential therapeutics for fibrotic disease in the liver, as well as other major organs.

描述（由申请人提供）：肝纤维化是一种影响全球数千万患者的疾病，是对病毒性肝炎B或C、过量饮酒、铁超负荷或肝外梗阻引起的慢性损伤的肝脏瘢痕形成反应，可进展为肝硬化、肝功能衰竭和死亡。事实上，由于丙型肝炎的流行和与非酒精性脂肪性肝炎相关的肝病发病率的增加，预计未来十年肝纤维化/肝硬化并发症的死亡人数将增加两倍。目前可用的疗法，包括抗病毒药物，在治疗潜在的纤维化方面基本无效，并且在大多数情况下，肝移植是唯一有效的治愈方法。肝纤维化，不论其病因，反映了相同的细胞和分子病理生理学。肝星状细胞的活化和转化为肌成纤维细胞是纤维化发生的主要事件，并沿着一个连续体进行，涉及细胞功能的进行性变化。细胞因子TGF？1在星状细胞活化和纤维化中起核心作用。转化生长因子1结合并激活其受体（ALK 5），ALK 5磷酸化并激活包括Smad 2在内的信号蛋白，导致纤维化标记基因的表达上调，如？SMA。 我们的长期目标是开发TGF？1受体作为纤维化肝脏疾病的潜在治疗方法。本申请的目的是鉴定此类抑制剂，并在两种临床相关的肝纤维化动物模型中对其进行评价。小分子抑制剂的TGF？1受体是肝脏以及其他主要器官纤维化疾病的潜在治疗剂。