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Role of SMPDL3B in obesity-associated non-alcoholic fatty liver disease

SMPDL3B 在肥胖相关非酒精性脂肪肝中的作用

基本信息

批准号：
10538925
负责人：
Shuxia Wang
金额：
$ 49.14万
依托单位：
UNIVERSITY OF KENTUCKY
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：
2022-07-01 至 2027-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10538925
关键词：
3-Dimensional Acids Affect Animal Model Animals Attenuated Back Binding CD36 Antigens CD36 gene Cell membrane Ceramides Data Development Diet Disease Disease Progression Down-Regulation Epidemic Fatty Liver Feedback Feeds Fibrosis GPI Membrane Anchors Human In Vitro Inflammation Inflammatory Knock-out Knowledge Kupffer Cells Lead Lipids Liver Liver Fibrosis Liver diseases Macrophage Activation Mediating Membrane Lipids Membrane Microdomains Membrane Proteins Metabolic Diseases Modeling Modification Obesity Organoids Pathogenesis Pathway interactions Patients Peptides Phenotype Process Production Proteins Reducing diet Risk Factors Rodent Role Signal Transduction Sphingomyelinase TLR4 gene Testing Therapeutic Thrombospondin 1 Western World base chronic liver disease cytokine in vitro Model in vivo knock-down macrophage monocyte mouse model nanoparticle new therapeutic target non-alcoholic fatty liver non-alcoholic fatty liver disease nonalcoholic steatohepatitis novel novel therapeutic intervention novel therapeutics obesity treatment overexpression peripheral blood receptor recruit targeted treatment therapy development

项目摘要

Obesity is an independent risk factor for development of non-alcoholic fatty liver disease (NAFLD). With the epidemic burden of obesity and metabolic diseases, NAFLD occurrence is steadily rising, along with the need for therapeutic options of this disease. Preliminary data from rodent and human studies provide strong evidence to support the hypothesis that monocyte/macrophage-derived TSP1 in obesity downregulates liver macrophage SMPDL3B and this downregulation feeds back to increase TSP1 binding to its receptor-CD36. This positive feedback loop together with SMPDL3B’s action on TLR pathways further amplifies liver macrophage pro-inflammatory signaling and leads to NAFLD progression. In this proposal, how SMPDL3B regulates CD36 function and then TSP1-CD36 dependent pro-inflammatory signaling in macrophages will be determined in Aim 1. The in vivo importance of macrophage SMPDL3B in NAFLD development and progression in both animal models and human liver organoids will be determined in Aim 2. Whether specific blockade of TSP1/CD36 interaction upregulates liver macrophage SMPDL3B and attenuates liver pro- inflammatory signaling and NAFLD development and progression will be determined in Aim 3. Completing these studies will provide novel information on the mechanisms by which suppressed macrophage SMPDL3B enhances liver macrophage pro-inflammatory signaling and its critical role in the progression of obesity- associated NAFLD to NASH. Further, testing a novel therapeutic application of a peptide nanoparticle conjugate to block TSP1/CD36 interaction in obesity-associated NASH in vivo will have translational significance.

肥胖是发展为非酒精性脂肪性肝病(NAFLD)的独立危险因素。与肥胖和代谢性疾病的流行负担，非酒精性脂肪肝的发病率正在稳步上升，随着需求的增加关于这种疾病的治疗选择。来自啮齿动物和人类研究的初步数据提供了强有力的支持肥胖患者单核/巨噬细胞来源的TSP1下调肝脏功能的证据巨噬细胞SMPDL3B和这种下调反馈增加TSP1与其受体CD36的结合。这个正反馈环与SMPDL3B在TLR通路上的作用一起进一步放大肝脏巨噬细胞的促炎信号并导致NAFLD的进展。在这份提案中，SMPDL3B如何调节CD36功能，然后TSP1-CD36依赖巨噬细胞的促炎信号巨噬细胞SMPDL3B在NAFLD发生和发展中的体内重要性在动物模型和人类肝脏有机化合物中的进展将在目标2中确定。阻断TSP1/CD36相互作用上调肝巨噬细胞SMPDL3B，抑制肝细胞病变炎症信号和NAFLD的发展和进展将在目标3中确定。完成这些研究将为抑制巨噬细胞SMPDL3B的机制提供新的信息增强肝巨噬细胞促炎信号及其在肥胖进展中的关键作用将NAFLD与NASH关联。此外，测试多肽纳米颗粒的一种新的治疗应用结合阻断肥胖相关NASH体内TSP1/CD36的相互作用将具有翻译作用意义。