Genetic and Environmental Determinants of GPRC6A Regulation of Energy Metabolism Using Genetically Engineered Mice and Systems Biology

GPRC6A 能量代谢调节的遗传和环境决定因素利用基因工程小鼠和系统生物学

• 批准号: 10544498
• 负责人: LU LU
• 金额: $ 49.59万
• 依托单位: UNIVERSITY OF TENNESSEE HEALTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10544498
• 关键词: Address; Adipocytes; Affect; Agonist; Amino Acids; Biochemical Pathway; Biochemical Process; Biological; Cardiovascular Diseases; Cells; Clinical; Collection; Communication; Complex; Data; Development; Diet; Disease Progression; Energy Metabolism; Enterocytes; Environment; Environmental Risk Factor; Ethnic Population; FGF21 gene; Family; Fatty acid glycerol esters; G-Protein-Coupled Receptors; GPRC6A gene; Gene Modified; Genes; Genetic; Genetic Polymorphism; Genetically Engineered Mouse; Genotype; Goals; Hepatic; Hepatocyte; High Fat Diet; Homeostasis; Hormones; Human; Hyperlipidemia; Hypertension; Inbred Strains Mice; Inbreeding; Insulin; Interleukin-6; Intestines; Knock-in; Knock-in Mouse; Knockout Mice; Knowledge; Lead; Ligands; Link; Liver; LoxP-flanked allele; Mediating; Metabolic; Metabolic Diseases; Metabolic Pathway; Metabolic syndrome; Metabolism; Molecular; Molecular Genetics; Molecular Target; Multiple Abnormalities; Mus; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Organ; Osteocalcin; Pathogenesis; Pathway interactions; Phenotype; Physiology; Population; Predisposition; Prevalence; Prevention; Recombinants; Regulation; Reproducibility; Resources; Risk; Role; Signal Pathway; Skeletal Muscle; Structure of beta Cell of islet; System; Systems Biology; Testing; Testosterone; Tissues; Transgenic Mice; Variant; blood glucose regulation; detection of nutrient; experimental study; fibroblast growth factor 21; gain of function; gene network; genetic approach; genetic architecture; glucagon-like peptide 1; glucose metabolism; glucose tolerance; improved; insight; leydig interstitial cell; lipid metabolism; metabolic phenotype; mouse genetics; mouse model; network models; non-alcoholic fatty liver disease; novel; novel therapeutics; pharmacologic; preclinical study; prevent; prototype; racial disparity; response; segregation; trait; transcriptomics; translational potential; treatment response

Metabolic syndrome (MetS) is a complex trait characterized by multiple abnormalities in glucose and fat metabolism, involving incompletely understood biological networks between various organs, and influenced by genetic and environmental (GXE) interactions. GPRC6A is a nutrient sensing G-protein coupled receptor implicated in the unique regulation of energy metabolism. In genetically engineered mouse models (GEMMs), GPRC6A regulates glucose and fat metabolism and prevents high fat diet (HFD) induced metabolic complications through direct tissue-specific effects and the release of hormones that coordinate metabolic functions between organs. The complexity of the cellular and systemic metabolic networks regulated by GPRC6A, the variable phenotypes in GEMMs, and the limited understanding of GPRC6A functions in humans are critical barriers to defining the role of GPRC6A in preventing and treating MetS and its complications. Our central hypothesis is that GXE interactions influence GPRC6A regulation of energy homeostasis. Aim 1 will test the hypothesis that GXE inter- actions modify GPRC6A regulation of glucose and fat metabolism in the liver and other metabolically active organs using GEMMs and a reductionist approach. Experiments will use wild-type GPRC6A-KGRKLP and GPRC6A null mice, HFD, and GPRC6A agonists to explore the effects of HFD and loss- and gain-of GPRC6A function on energy metabolism in mice. The functional significance of the recently evolved human GPRC6A_KGKY genetic polymorphism will be tested in a “humanized” Gprc6a_KGKY_knockin mouse. We will characterize hepatocyte-specific Gprc6a knockout mice (Gprc6aliver-cko) to investigate GPRC6A’s function in liver, as a prototypic organ controlling glucose and fat metabolism. In Aim 2, we will use groundbreaking resources for systems genetics systems to test hypothesis that genetic backgrounds modify the metabolic effects of GPRC6A and HFD. We will collect metabolic phenotypes and molecular expression data from the livers of BXD recombinant inbred lines treated with a HFD and the GPRC6A agonist, osteocalcin (Ocn). Then we will apply systems biology approaches to define signaling pathways, metabolic processes and gene networks involving GPRC6A regulation of hepatic fat and glucose metabolism. Cell, molecular and mouse genetic approaches will validate these pathways and net- works predicted by systems biology. The predictive power of experimental and computational systems biology approaches to incorporate and integrate distinct levels of information and scientific knowledge of complex systems created by GPRC6A will improve the rigor and reproducibility of preclinical studies of GPRC6A effects on MetS. Our impact will be to: 1) establish the organ-specific functions of GPRC6AKGRKLP and GPRC6AKGKY variants and determine if these polymorphisms alter the susceptibility to and treatment responses of MetS and its metabolic complications; 2) identify the GPRC6A-regulated gene networks controlling glucose and fat metabolism and determine the genetic modifiers that influence the effects of GPRC6A and HFD on MetS; and 3) validate GPRC6A as a unique molecular target for understanding the pathogenesis and treatment of MetS.

代谢综合征 (MetS) 是一种复杂的特征，其特征是葡萄糖和脂肪代谢的多种异常，涉及各个器官之间不完全了解的生物网络，并受到遗传和环境 (GXE) 相互作用的影响。GPRC6A 是一种营养感应 G 蛋白偶联受体。在基因工程小鼠模型 (GEMM) 中，GPRC6A 具有独特的能量代谢调节作用，可通过直接的组织特异性作用和释放GPRC6A 调节的细胞和全身代谢网络的复杂性、GEMM 的可变表型以及对人类 GPRC6A 功能的有限了解是确定 GPRC6A 在预防和治疗 MetS 中的作用的关键障碍。我们的中心假设是 GXE 相互作用影响 GPRC6A 对能量稳态的调节，目标 1 将检验 GXE 相互作用改变 GPRC6A 对葡萄糖和脂肪代谢的调节这一假设。实验将使用野生型 GPRC6A-KGRKLP 和 GPRC6A 缺失小鼠、HFD 和 GPRC6A 激动剂来探索 HFD 以及 GPRC6A 功能丧失和增强的影响。最近进化的人类 GPRC6A_KGKY 基因多态性的功能意义将在“人源化”中进行测试。 Gprc6a_KGKY_knockin 小鼠。我们将表征肝细胞特异性 Gprc6a 敲除小鼠 (Gprc6aliver-cko)，以研究 GPRC6A 作为控制葡萄糖和脂肪代谢的原型器官在肝脏中的功能。在目标 2 中，我们将使用系统遗传学系统的突破性资源来检验假设。遗传背景会改变 GPRC6A 和 HFD 的代谢效应 我们将从肝脏收集代谢表型和分子表达数据。然后，我们将应用系统生物学方法来定义涉及 GPRC6A 肝脏脂肪和葡萄糖代谢调节的信号通路、代谢过程和基因网络。小鼠遗传方法将验证系统生物学预测的这些途径和网络的预测能力，以整合和整合 GPRC6A 创建的复杂系统的不同水平的信息和科学知识。将提高 GPRC6A 对 MetS 影响的临床前研究的严谨性和可重复性 我们的影响将是：1) 建立 GPRC6AKGRKLP 和 GPRC6AKGKY 变体的器官特异性功能，并确定这些多态性是否改变 MetS 及其治疗反应。代谢并发症；2) 确定控制葡萄糖和脂肪代谢的 GPRC6A 调节基因网络，并确定影响 GPRC6A 作用的遗传修饰因子。和 HFD 对 MetS 的影响；3) 验证 GPRC6A 作为了解 MetS 发病机制和治疗的独特分子靶点。

项目成果

The carboxylation status of osteocalcin has important consequences for its structure and dynamics.

• DOI: 10.1016/j.bbagen.2020.129809
• 发表时间: 2021-03
• 期刊: Biochimica et biophysica acta. General subjects
• 作者: Kapoor K;Pi M;Nishimoto SK;Quarles LD;Baudry J;Smith JC
• 通讯作者: Smith JC

Ace2 and Tmprss2 Expressions Are Regulated by Dhx32 and Influence the Gastrointestinal Symptoms Caused by SARS-CoV-2.

• DOI: 10.3390/jpm11111212
• 发表时间: 2021-11-16
• 期刊: Journal of personalized medicine
• 作者: Xu F;Gao J;Orgil BO;Bajpai AK;Gu Q;Purevjav E;Davenport AS;Li K;Towbin JA;Black DD;Pierre JF;Lu L
• 通讯作者: Lu L

Explaining Divergent Observations Regarding Osteocalcin/GPRC6A Endocrine Signaling.

• DOI: 10.1210/endocr/bqab011
• 发表时间: 2021-04-01
• 期刊: Endocrinology
• 影响因子: 4.8
• 作者: Pi M;Nishimoto SK;Darryl Quarles L
• 通讯作者: Darryl Quarles L