Investigating the regulation of central metabolism as key to human health and disorders through the association of PASK, USF1 and ATXN2 with phenotypes and disorders in the All of Us database

通过 PASK、USF1 和 ATXN2 与 All of Us 数据库中表型和疾病的关联，研究中枢代谢的调节作为人类健康和疾病的关键

• 批准号: 10658609
• 负责人: Julianne H. Grose
• 金额: $ 11.36万
• 依托单位: BRIGHAM YOUNG UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-03-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10658609
• 关键词: Affect; Alleles; Anabolism; Blood Glucose; COVID-19; COVID-19 severity; COVID-19 susceptibility; Carbon; Cardiovascular system; Cause of Death; Cell Respiration; Cells; Coronary heart disease; Data; Data Set; Databases; Development; Diabetes Mellitus; Diet; Disease; Electronic Health Record; Exercise; Fatty acid glycerol esters; Foundations; Genes; Glucose; Goals; Health; Heart; Homeostasis; Human; Hyperlipidemia; Individual; Informatics; Insulin; Link; Lipids; Liver; Malignant Neoplasms; Measures; Medical Research; Metabolic; Metabolic Diseases; Metabolic Pathway; Metabolism; Molecular; Mus; Myocardial Infarction; Neurodegenerative Disorders; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Outcome; Pathway interactions; Pattern; Phenotype; Population; Predisposition; Prevention; Principal Component Analysis; Production; Protein Kinase; Proteins; Race; Regulation; Resistance; Respiration; Risk Factors; Role; SCA2 protein; Sensory; Stroke; Surveys; System; Triglyceride Metabolism; Triglycerides; USF1 gene; United States; Variant; Weight; Yeasts; admixture mapping; base; detection of nutrient; fitbit; genome sequencing; human disease; lipid biosynthesis; metabolic rate; phenome; phenotypic data; phosphatidylinositol 3' -kinase-associated serine kinase; rare variant; research study; respiratory; sugar; western diet; whole genome

Metabolic dysregulation lies at the heart of most disorders, from hyperlipidemia and diabetes to cancer and neurodegenerative disorders. Sensory protein kinases, which sense cellular metabolites and regulate metabolism accordingly, lie at the heart of metabolic homeostasis. PAS kinase (PASK) is a nutrient sensing protein kinase that regulates partitioning of glucose to lipid production versus respiratory metabolism. PASK deficient mice are resistant to liver triglyceride accumulation and display increased respiration when on a high-fat or high-fat high-sugar diet. In addition, PASK deficient mice display altered insulin metabolism in several studies, with PASK alleles associated with Maturity Onset Diabetes of the Young (MODY) in a small familial study. Our long-term goal is to characterize the role of PASK in human disease, including the molecular pathways by which it regulates central metabolism. Our short-term goal described herein is to conduct the first large-scale analysis of PASK alleles (and alleles of its protein substrates) associated with human disease. The Grose lab has identified two PASK substrates associated with lipid and respiratory metabolism, namely Upstream Stimulatory Factor 1 (USF1) and Ataxin-2 (ATXN2), the primary focus of our current R15. Herein Dr. Julianne Grose, a molecular biologist, teams up with Dr. Mary Davis, a biomedical informaticist and human geneticist, to uncover the influence of PASK, USF1, and ATXN2 variants on a variety of human phenotypes and classes of disease, from hyperlipidemia and diabetes to cancer and neurodegenerative disorders. The All of Us dataset makes this possible. All of Us provides phenotypes from electronic health records, basic vitals, surveys, exercise data (e.g. Fitbit) and COVID- 19 results, as well as whole genome sequencing. In our first Aim we will analyze common and rare variants in PASK, USF1, and ATXN2 compared to triglycerides, weight, cardiovascular measures, exercise levels and COVID-19 results. In our second Aim, we will perform a phenome-wide association study (PheWAS), in which variants in PASK, USF1, and ATXN2 will be regressed against phenotypes from electronic health record data. In addition to the wide variety of phenotypic data, the ancestral diversity represented by the individuals in the dataset will allow us to identify patterns and variants that differ or are similar across ancestry, identifying both multigene effects due to ancestry and conserved effects common to humankind. Combined, the mechanistic results from our R15 and the informatic results from the supplement described herein further our progress towards holistic treatments and preventions for human disorders.

代谢失调是大多数疾病的核心，从高脂血症和糖尿病， 癌症和神经退行性疾病。感觉蛋白激酶，感觉细胞代谢物 并相应地调节新陈代谢，是代谢稳态的核心。PAS激酶（PASK）是 一种营养感应蛋白激酶，调节葡萄糖分配到脂质产生， 呼吸代谢PASK缺陷型小鼠对肝脏甘油三酯积累具有抗性， 高脂肪或高脂肪高糖饮食时呼吸增加。此外，PASK缺陷小鼠 在几项研究中显示出胰岛素代谢的改变，PASK等位基因与成熟开始相关 年轻人糖尿病（MODY）在一项小型家庭研究中。我们的长期目标是描述 PASK在人类疾病中的作用，包括其调节中枢代谢的分子途径。 本文描述的我们的短期目标是进行PASK等位基因的第一次大规模分析（和 其蛋白质底物的等位基因）与人类疾病相关。 Grose实验室已经确定了两种与脂质和呼吸系统相关的PASK底物， 代谢，即上游刺激因子1（USF 1）和共济失调蛋白-2（ATXN 2）， 我们当前的R15。分子生物学家朱丽安·格罗斯博士与分子生物学家玛丽·戴维斯博士合作， 生物医学信息学家和人类遗传学家，揭示PASK，USF 1和ATXN 2的影响 各种人类表型和疾病类别的变体，从高脂血症和糖尿病到 癌症和神经退行性疾病。All of Us数据集使这成为可能。我们所有人提供 来自电子健康记录、基本生命体征、调查、运动数据（如Fitbit）和COVID的表型- 19个结果，以及全基因组测序。在我们的第一个目标中，我们将分析常见和罕见 与甘油三酯、体重、心血管指标相比，PASK、USF 1和ATXN 2的变异， 运动水平和COVID-19结果。在我们的第二个目标中，我们将执行全现象关联 研究（PheWAS），其中PASK、USF 1和ATXN 2中的变体将针对表型进行回归 电子健康记录数据。除了各种各样的表型数据外， 数据集中个体所代表的多样性将使我们能够识别出 不同或相似的祖先，确定由于祖先和保守的多基因效应 对人类的共同影响。结合起来，我们的R15和信息学的机械结果 本文所述的补充剂的结果促进了我们对整体治疗的进展， 预防人类疾病。

项目成果

The effects of diet and sex in amyotrophic lateral sclerosis.

• DOI: 10.1016/j.neurol.2019.09.008
• 发表时间: 2020-05
• 期刊: Revue neurologique
• 影响因子: 3
• 作者: Pape JA;Grose JH
• 通讯作者: Grose JH

A comprehensive protein-protein interactome for yeast PAS kinase 1 reveals direct inhibition of respiration through the phosphorylation of Cbf1.

• DOI: 10.1091/mbc.e13-10-0631
• 发表时间: 2014-07-15
• 期刊: Molecular biology of the cell
• 影响因子: 3.3
• 作者: DeMille D;Bikman BT;Mathis AD;Prince JT;Mackay JT;Sowa SW;Hall TD;Grose JH
• 通讯作者: Grose JH

PAS kinase is activated by direct SNF1-dependent phosphorylation and mediates inhibition of TORC1 through the phosphorylation and activation of Pbp1.

PAS激酶通过直接依赖SNF1的磷酸化激活，并通过PBP1的磷酸化和激活介导Torc1抑制。

• DOI: 10.1091/mbc.e14-06-1088
• 发表时间: 2015-02-01
• 期刊: Molecular biology of the cell
• 影响因子: 3.3
• 作者: DeMille D;Badal BD;Evans JB;Mathis AD;Anderson JF;Grose JH
• 通讯作者: Grose JH

PAS kinase: a nutrient sensing regulator of glucose homeostasis.

PAS激酶：葡萄糖稳态的营养传感调节剂。

• DOI: 10.1002/iub.1219
• 发表时间: 2013-11
• 期刊: IUBMB LIFE
• 影响因子: 4.6
• 作者: DeMille, Desiree;Grose, Julianne H.
• 通讯作者: Grose, Julianne H.

Per-Arnt-Sim Kinase (PASK) Deficiency Increases Cellular Respiration on a Standard Diet and Decreases Liver Triglyceride Accumulation on a Western High-Fat High-Sugar Diet.

Per-Arnt-Sim 激酶 (PASK) 缺乏会增加标准饮食中的细胞呼吸，并减少西方高脂肪高糖饮食中肝脏甘油三酯的积累。

• DOI: 10.3390/nu10121990
• 发表时间: 2018
• 期刊: Nutrients
• 影响因子: 5.9
• 作者: Pape,JennyA;Newey,ColleenR;Burrell,HaleyR;Workman,Audrey;Perry,Katelyn;Bikman,BenjaminT;Bridgewater,LauraC;Grose,JulianneH
• 通讯作者: Grose,JulianneH