Nuclear receptors and their Coactivators as Mediators of Systems Metabolism

核受体及其共激活剂作为系统代谢的调节剂

• 批准号: 10153756
• 负责人: BERT W O'MALLEY
• 金额: $ 150.58万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10153756
• 关键词: Address; Adipocytes; Adipose tissue; Adult; Advanced Development; Agriculture; Amplifiers; Anabolism; Animals; Area; Bioinformatics; Brain; Budgets; Chronic; Clinical; Complex; Consumption; Coronary heart disease; Degenerative polyarthritis; Deposition; Desire for food; Development; Disease; Doctor of Medicine; Doctor of Philosophy; Dyslipidemias; Epidemic; Equilibrium; Event; Evolution; Exposure to; FOXO1A gene; Family; Fasting; Fatty Liver; Fatty acid glycerol esters; Food; Food Energy; Gap Junctions; Gatekeeping; Genes; Genetic Transcription; Hepatic; Homeostasis; Hormone use; Human; Hypertension; Hypertrophy; Hypothalamic structure; Individual; Inflammatory; Insulin Resistance; Interdisciplinary Study; Interruption; Knowledge; Liver; Maintenance; Malignant Neoplasms; Mammals; Mediating; Mediator of activation protein; Medical Care Costs; Metabolic; Metabolic Diseases; Metabolism; Methods; Mission; Molecular; NCOA3 gene; National Institute of Diabetes and Digestive and Kidney Diseases; Nature; Non-Insulin-Dependent Diabetes Mellitus; Nuclear Hormone Receptors; Nuclear Receptors; Nutritional; Obesity; Obesity associated disease; Organ; Overnutrition; Overweight; PPAR alpha; PPAR gamma; Pathologic; Pattern; Peptides; Phenotype; Population; Program Research Project Grants; Public Health; Research; Role; STAT3 gene; Satiation; Scientist; Signal Transduction; Smoking; Steroid Receptors; Syndrome; System; Therapeutic; Tissues; Transcriptional Regulation; Triad Acrylic Resin; United States National Institutes of Health; Work; combat; energy balance; expectation; experience; feeding; hormonal signals; improved; macromolecule; metabolomics; molecular phenotype; mortality; novel therapeutic intervention; novel therapeutics; nuclear receptor coactivator 1; obesity treatment; phenotypic data; programs; response; steroid hormone receptor; transcription factor; transcriptional reprogramming

Overall -­ Project Summary    Obesity is approaching epidemic proportions as a nutritional and pathological disorder in the U.S. and is closely  associated  with  important  syndromes  including  type  2  diabetes,  insulin  resistance,  hepatic  steatosis,  dyslipidemias,  hypertension,  coronary  heart  disease,  osteoarthritis  and  cancer.  Obesity  rates  in  the  U.S.  have  continued  to  worsen  whereby  nearly  70%  of  the  adult  population  is  overweight  and  the  yearly  medical  cost  of  treatment  for  obesity-­related  disease  is  estimated  at  $190  billion,  currently  6X  the  annual  NIH  budget.  Consequently,  obesity  is  anticipated  to  overtake  smoking  as  the  most  preventable  cause  of  adult  mortality.  Therefore, public health initiatives focused on identifying therapeutic options to combat the detrimental effects of  obesity-­related disease rely on an improved understanding of how alterations in metabolic tissue crosstalk alters  metabolism  to  favor  energy  accretion  and  deposition.  Our  highly  synergistic  and  integrated  Program  Project  team has identified previously unappreciated molecular mechanisms that highlight the coordinated actions of the  hypothalamus (brain), liver and white adipose tissues as gatekeepers of metabolic energy balance that become  dysregulated by overnutrition. By focusing on the metabolic actions of the Steroid Receptor Coactivator (SRC)  family  as  amplifiers  of  nuclear  hormone  receptor  (NR)/transcription  factor  (TF)  function  in  this  triad  of  energy-­ responsive  tissues,  we  have  exposed  transcriptional  reprogramming  as  a  key  molecular  determinant  in  the  disruption  of  normal  energy  homeostasis  arising  from  chronic  exposure  to  caloric  excess.  Such  a  complex  metabolic regulatory axis, which involves the interplay of multiple tissue systems (i.e. brain, liver, adipose), and  underlying transcriptional machinery (NR/SRCs) that maintain their homeostatic balance, can only be adequately  studied by a multidisciplinary research team with unique, yet synergistic, expertise. Leveraging the collaborative  framework of the NIDDK P01 Program Project, we have assembled such a team of scientists who are dedicated  to the overall objective of understanding the ‘mechanisms’ for the downstream tissue-­specific metabolic functions  of NR/SRC action that govern whole body energy balance.

总体 - 项目摘要    在美国，肥胖症作为一种营养和病理性疾病已接近流行病的比例，并且与  与重要的综合征相关，包括 2 型糖尿病、胰岛素抵抗、肝脂肪变性、  血脂异常、高血压、冠心病、骨关节炎和癌症。  美国的肥胖率  持续恶化，近 70% 的成年人超重，每年的医疗费用  肥胖相关疾病的治疗费用估计为 1900 亿美元，目前是 NIH 年度预算的 6 倍。  因此，肥胖预计将超过吸烟，成为成人死亡最可预防的原因。  因此，公共卫生举措的重点是确定治疗方案，以对抗以下疾病的有害影响：  肥胖相关疾病依赖于对代谢组织串扰如何改变的更好的理解  新陈代谢有利于能量的积累和沉积。  我们高度协同和集成的计划项目  团队已经确定了以前未被重视的分子机制，这些机制强调了协调行动  下丘脑（大脑）、肝脏和白色脂肪组织作为代谢能量平衡的看门人  因营养过剩而失调。 通过关注类固醇受体辅激活剂 (SRC) 的代谢作用  家族作为核激素受体（NR）/转录因子（TF）的放大器，在能量三联体中发挥作用- 在反应组织中，我们已经揭示了转录重编程作为反应组织中的关键分子决定因素  由于长期摄入过多热量而破坏正常能量稳态。  如此复杂  代谢调节轴，涉及多个组织系统（即大脑、肝脏、脂肪）的相互作用，以及  维持其稳态平衡的底层转录机器（NR/SRC）只能被充分利用  由具有独特且协同专业知识的多学科研究团队进行研究。 利用协作  在 NIDDK P01 计划项目的框架下，我们组建了这样一个致力于奉献的科学家团队  总体目标是了解下游组织特异性代谢功能的“机制”  NR/SRC 作用控制全身能量平衡。