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 在美国，肥胖是可预防死亡的第二大原因。肥胖是一种复杂的营养问题 以及由能量不平衡驱动的遗传性疾病，是各种疾病的基本风险因素 病理包括冠状动脉疾病、糖尿病、非酒精性脂肪性肝病和动脉粥样硬化。 在不同组织中导致肥胖相关疾病的细胞和分子机制还不完全清楚。 这对开发有效和高效的治疗方法构成了障碍。阿洛平 是一种新近鉴定的肝脏和大脑衍生的多肽激素，对燃料有强大的作用 外周组织中的底物代谢。肥胖症和糖尿病患者肾上腺素水平显著降低 这种下降与肥胖增加和葡萄糖稳态受损有关。 此外，肾上腺素缺乏与肝脏肥胖症的发生有关。 例如NAFLD和NASH。在这个团契申请中，我们将确定分子信号通路 了解肾上腺素在肝脏燃料代谢中的作用，并探讨其对NAFLD和 纳什。在目标1中，我们将确定肾上腺素如何与细胞膜受体GPR19结合来调节 肝细胞燃料代谢。在目标2中，我们将确定GPR19是否为保护作用所必需的 阿屈平抗肝损伤。通过结合尖端的新陈代谢技术和全面的培训 计划，这笔奖学金将使我为代谢研究和科学研究的下一阶段做准备 教育。