Targeting the hepatic adropin signaling pathway in obesity

靶向肥胖中的肝脏 adropin 信号通路

• 批准号: 10677279
• 负责人: Bellina Mushala
• 金额: $ 4.32万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10677279
• 关键词: Address; Animal Model; Apoptosis; Atherosclerosis; Biochemical; Bioenergetics; Biological Process; Brain; Cardiac; Cell membrane; Cells; Complex; Coronary Arteriosclerosis; Defect; Development; Diabetes Mellitus; Diet; Disease; Disease Progression; Education; Endothelium; Energy Metabolism Pathway; Enzymes; Essential Genes; Exhibits; Fatty Acids; Fatty Liver; Fatty acid glycerol esters; Fellowship; Fibrosis; G-Protein-Coupled Receptors; Genetic Diseases; Glucose; Goals; Heart; Hepatic; Hepatocyte; Histologic; Homeostasis; Immunohistochemistry; Impairment; In Vitro; Inflammation; Inflammatory Response; Knock-out; Knockout Mice; Ligands; Link; Lipids; Liver; Measures; Mediating; Mediator; Metabolic; Metabolic Diseases; Metabolism; Molecular; Null Lymphocytes; Nutrient; Nutrition Disorders; Obesity; Obesity associated disease; Obesity associated liver disease; Orphan; PPAR gamma; Pathologic; Pathology; Peripheral; Phenotype; Population; Prevalence; Recombinants; Regulation; Regulatory Pathway; Research; Resistance; Risk Factors; Role; Signal Pathway; Signal Transduction; Techniques; Testing; Therapeutic Effect; Tissues; Training; United States; Up-Regulation; Western Blotting; Wild Type Mouse; blood glucose regulation; career; design; diabetic; effective therapy; human subject; in vivo; lipid metabolism; liver development; liver injury; mouse model; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; novel; oxidation; oxidative damage; peptide hormone; preventable death; protective effect; receptor; response; uptake

PROJECT SUMMARY/ABSTRACT Obesity is the second leading cause of preventable death in the United States. Obesity is a complex nutritional and genetic disorder that is driven by energy imbalances, and serves as a fundamental risk factor in various pathologies including coronary artery disease, diabetes, non-alcoholic fatty liver disease, and atherosclerosis. The cellular and molecular mechanisms that drive obesity-related disease in different tissues are not fully elucidated, and this represents an impediment to the development of effective and efficient treatments. Adropin is a recently characterized liver- and brain-derived peptide hormone that exerts powerful effects on fuel substrate metabolism in peripheral tissues. Adropin levels are significantly reduced in obese and diabetic human subjects, and this decrease is linked to increased adiposity and impaired glucose homeostasis. Furthermore, adropin depletion has been linked with the development of liver-associated obesity diseases such as NAFLD and NASH. In this fellowship application, we will determine the molecular signaling pathways underlying adropin function in liver fuel metabolism, and investigate its protective effects against NAFLD and NASH. In Aim 1, we will determine how adropin associates with the cell membrane receptor GPR19 to regulate hepatocyte fuel metabolism. In Aim 2, we will determine if GPR19 is necessary for the protective effects of adropin against hepatic injury. By combining cutting-edge metabolic techniques and a comprehensive training plan, this fellowship will allow me to prepare for the next stage of my career in metabolic research and scientific education.

项目摘要/摘要 肥胖是美国可预防死亡的第二大原因。肥胖是一种复杂的营养 以及由能量失衡驱动的遗传疾病，并且是各种基本危险因素 病理学，包括冠状动脉疾病，糖尿病，非酒精性脂肪肝病和动脉粥样硬化。 在不同组织中驱动肥胖相关疾病的细胞和分子机制并非完全 阐明，这代表了有效和有效治疗的发展的障碍。 adropin 是最近表征的肝和脑衍生的肽激素，对燃料产生了强大的影响 外周组织中的底物代谢。肥胖和糖尿病患者的adropin水平显着降低 人类受试者，这种减少与增加的肥胖和葡萄糖稳态受损有关。 此外，adropin耗竭与肝相关肥胖症的发展有关 例如Nafld和Nash。在此奖学金应用中，我们将确定分子信号通路 肝燃料代谢中的潜在adropin功能，并研究其针对NAFLD和的保护作用 纳什。在AIM 1中，我们将确定Adropin如何与细胞膜受体GPR19相关联 肝细胞燃料代谢。在AIM 2中，我们将确定GPR19是否需要 反对肝损伤的adropin。通过结合尖端的代谢技术和全面的培训 计划，该奖学金将使我为我的代谢研究和科学研究的下一阶段做准备 教育。