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: 10674678
• 负责人: Russell Paul Goodman
• 金额: $ 13.01万
• 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/10674678
• 关键词: Biological Markers; Blood Glucose; Cytosol; Data; Disease; FGF21 gene; Faculty; 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; Pathogenesis; Physiological; Physiology; Plasma; Population; Public Health; Reaction; Research; Research Project Grants; Source; Stress; Testing; Tissues; Transcript; Triglycerides; United States National Institutes of Health; Variant; Work; circulating biomarkers; cofactor; cohort; fatty liver disease; fibroblast growth factor 21; gene function; genetic architecture; genetic variant; genome wide association study; human disease; in vivo; innovation; insight; liver metabolism; member; new therapeutic target; novel; oxidation; 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是一种代谢辅因子，其沿着其氧化形式NAD+，参与数百种代谢。 还原/氧化（氧化还原）反应，为细胞代谢提供动力。NADH水平的相对增加 促进还原并且被认为是代谢应激（“还原应激”）的来源，尽管 由于缺乏工具，还原应力在体内的精确结果一直难以研究。 来精确控制NADH水平。使用一种新开发的工具可以精确地组织- 由于NADH的特异性操作，我们最近证明代谢产物β-羟基丁酸是一种 肝还原性应激生物标志物，肝还原性应激与许多 重要的代谢特征。这项工作的长期目标是更好地了解遗传 结构的肝脏还原应激，并在这样做都扩大了我们的理解，其代谢 和生理后果，并确定潜在的基因，可能有针对性地改变 以有益的方式进行新陈代谢。我们的中心假设是肝还原酶的遗传调节因子 应激可以通过结合现有的基因分型在多样性远系繁殖（DO）小鼠群中鉴定 和RNAseq数据，测量小鼠血浆β-羟基丁酸水平。这样做的理由 建议是，已经证明还原应激影响许多重要的代谢特征， 确定还原应激的遗传调节因子将为这一重要的代谢过程提供关键调节因子。 参数，并且是重要的，因为这将激发新的治疗靶向范例。这项工作是 创新之处在于它利用了血浆β-羟基丁酸是肝脏NADH生物标志物的新见解 水平，以使用来自遗传多样性小鼠队列的血浆来鉴定该水平的因果遗传影响。 参数.