Identifying genetic regulators of hepatic reductive stress in diversity outbred mice

鉴定多样性远交小鼠肝脏还原应激的遗传调节因子

• 批准号: 10354824
• 负责人: Russell Paul Goodman
• 金额: $ 12.99万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10354824
• 关键词: Biological Markers; Blood Glucose; Cytosol; Data; Disease; FGF21 gene; Faculty; Fatty Liver; Foundations; Future; General Hospitals; Genes; Genetic; Genetic Determinism; Genetic Variation; Genome; Genotype; Goals; Grant; Heart; Hepatic; Human; Hydroxybutyrates; Life; Link; Liver; Massachusetts; Measurement; Measures; Metabolic; Metabolic Pathway; Metabolic stress; Metabolism; Mission; Mus; NADH; Organelles; Other Genetics; Oxidation-Reduction; Oxides; Pathogenesis; Physiological; Physiology; Plasma; Population; Public Health; Reaction; Research; Research Project Grants; Source; Testing; Tissues; Transcript; Triglycerides; United States National Institutes of Health; Variant; Work; circulating biomarkers; cofactor; cohort; gene function; genetic architecture; genetic variant; genome wide association study; human disease; in vivo; innovation; insight; liver metabolism; member; new therapeutic target; novel; stress reduction; tool; trait; transcriptome sequencing

NADH is a metabolic cofactor that, along with its oxidized form, NAD+, participates in hundreds of reduction/oxidation (redox) reactions that power cellular metabolism. A relative increase in NADH levels promotes reduction and is thought to be a source of metabolic stress (“reductive stress”), though the precise consequences of reductive stress in vivo have been difficult to study due to a lack of tools with which to precisely manipulate NADH levels. Using a newly developed tool that enables precise tissue- specific manipulation of NADH, we recently demonstrated that the metabolite -hydroxybutyrate was a biomarker of hepatic reductive stress, and that hepatic reductive stress was causally linked to a number of important metabolic traits. The long-term goal of this work to better understand the genetic architecture of hepatic reductive stress, and in doing so both expand our understanding of its metabolic and physiologic consequences and to identify potential genes that might be targeted to alter metabolism in beneficial ways. Our central hypothesis is that genetic regulators of hepatic reductive stress can be identified in the diversity outbred (DO) mouse cohort by combining existing genotyping and RNAseq data with measurements of mouse plasma -hydroxybutyrate levels. The rationale for this proposal is that, having demonstrated that reductive stress influences many important metabolic traits, identifying genetic regulators of reductive stress will provide key regulators of this important metabolic parameter and is significant as this will inspire novel therapeutic targeted paradigms. This work is innovative in that it leverages new insight that plasma -hydroxybutyrate is biomarker of hepatic NADH levels to use plasma from a genetically diverse mouse cohort to identify causal genetic influences of this parameter.

NADH 是一种代谢辅助因子，与其氧化形式 NAD+ 一起参与数百种代谢过程 为细胞新陈代谢提供动力的还原/氧化（氧化还原）反应。 NADH 水平相对增加 促进还原并被认为是代谢应激（“还原应激”）的一个来源，尽管 由于缺乏研究还原应激的工具，很难研究体内还原应激的精确后果。 从而精确控制 NADH 水平。使用新开发的工具可以实现精确的组织 通过对 NADH 的特定操作，我们最近证明了代谢物 α-羟基丁酸是一种 肝脏还原应激的生物标志物，并且肝脏还原应激与许多因素存在因果关系 的重要代谢特征。这项工作的长期目标是更好地了解遗传 肝脏还原应激的结构，这样做既扩展了我们对其代谢的理解 和生理后果，并确定可能有针对性地改变的潜在基因 以有益的方式进行新陈代谢。我们的中心假设是肝还原的遗传调节因子 通过结合现有的基因分型，可以在多样性远交 (DO) 小鼠群体中识别压力 和 RNAseq 数据以及小鼠血浆 α-羟基丁酸水平的测量。这样做的理由 建议是，在证明还原应激影响许多重要的代谢特征后， 识别还原应激的遗传调节因子将为这一重要代谢提供关键调节因子 参数并且很重要，因为这将激发新的治疗目标范例。这部作品是 创新之处在于它利用了血浆 α-羟基丁酸是肝脏 NADH 生物标志物的新见解 水平使用来自遗传多样性小鼠群体的血浆来识别这种因果遗传影响 范围。