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，其氧化形式NAD+参与了数百个 功率细胞代谢的还原/氧化（氧化还原）反应。 NADH水平的相对增加 促进还原，被认为是代谢压力的来源（“还原应力”），尽管 由于缺乏工具，因此很难研究体内压力减轻的确切后果 精确操纵NADH水平。使用新开发的工具，该工具可实现精确的组织 NADH的具体操作，我们最近证明了代谢物-羟基丁酸是一个 肝素的生物标志物减轻了压力，肝脏减轻的压力有时与数量有关 重要的代谢特征。这项工作的长期目标是更好地了解通用 肝素的结构减轻了压力，这两者都扩大了我们对代谢的理解 和生理后果，并确定可能针对改变的潜在基因 以有益的方式代谢。我们的中心假设是肝脏减少的遗传调节剂 可以通过组合现有的基因分型来在多样性（DO）小鼠队列中识别压力 和RNASEQ数据，用于测量小鼠血浆-羟基丁酸水平。理由 建议是，表明压力减轻会影响许多重要的代谢特征，因此 确定压力减轻的遗传调节因子将为这一重要代谢提供关键调节剂 参数很重要，因为这将激发新的治疗性靶向范例。这项工作是 创新性的是，它利用了新见解，即等离子体-Hydroxybutyrate是肝nadh的生物标志物 使用来自遗传多样的小鼠队列的血浆来鉴定该因果的遗传影响 范围。