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

基本信息

批准号：
10421277
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
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-01 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10421277
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 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

项目摘要

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程度，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、美国的血脂异常、高血压、冠心病、骨关节炎和癌症的发病率很高。持续恶化，因此近 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。肥胖预计将取代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理解我们的高度协同和综合的计划项目。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守门人，营养过剩导致的失调通过关注类固醇受体辅激活因子 (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性组织中，我们发现转录重编程是反应组织中的关键分子决定因素长期摄入过多的热量会破坏正常的能量稳态。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制（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。在 NIDDK P01 计划项目的框架下，我们组建了这样一支敬业的科学家团队。总体目标是了解下游组织特异性代谢功能的“机制” NR/SRC 调节全身能量平衡的作用。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Steroid receptor coactivator-3 as a target for anaplastic thyroid cancer.

类固醇受体辅激活因子 3 作为甲状腺未分化癌的靶标。

DOI：
10.1530/erc-19-0482
发表时间：
2020-01-01
期刊：
Endocrine-related cancer
影响因子：
3.9
作者：
Woo Kyung Lee;Won Gu Kim;L. Fozzatti;Sunmi Park;Li Zhao;M. Willingham;D. Lonard;B. O’Malley;S. Cheng
通讯作者：
S. Cheng

12-h clock regulation of genetic information flow by XBP1s.

XBP1 对遗传信息流的 12 小时时钟调节。

DOI：
发表时间：
2020
期刊：
影响因子：
9.8
作者：
Pan, Yinghong;Ballance, Heather;Meng, Huan;Gonzalez, Naomi;Kim, Sam;Abdurehman, Leymaan;York, Brian;Chen, Xi;Schnytzer, Yisrael;Levy, Oren;Dacso, Clifford C;McClung, Colleen A;O'Malley, Bert W;Liu, Silvia;Zhu, Bokai
通讯作者：
Zhu, Bokai

The bile acid induced hepatokine orosomucoid suppresses adipocyte differentiation.

胆汁酸诱导的肝因子类粘蛋白抑制脂肪细胞分化。