Mechanisms of metabolic, inflammatory and healthspan enhancement by 17a-estradiol

17a-雌二醇增强代谢、炎症和健康寿命的机制

• 批准号: 9790886
• 负责人: Michael B Stout
• 金额: $ 24.87万
• 依托单位: UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-30 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9790886
• 关键词: 3-Phosphoinositide Dependent Protein Kinase-1; 5' -AMP-activated protein kinase; Address; Adipose tissue; Aerobic Exercise; Aging; Animals; Applications Grants; Area; Binding; Bioinformatics; Biological Assay; Biological Models; Body Weight decreased; Ca(2+)-Calmodulin Dependent Protein Kinase; Caloric Restriction; Cardiovascular system; Cell Culture Techniques; Chronic; Chronic Disease; Collaborations; Development; Diabetes Mellitus; Disease; Drug or chemical Tissue Distribution; Elderly; Estradiol; Estrogen Receptors; Exposure to; FRAP1 gene; Faculty; Flow Cytometry; Functional disorder; Funding; Future; Goals; Homeostasis; Hormones; Human; Immunofluorescence Immunologic; Immunohistochemistry; Inflammation; Inflammatory; Insulin; Interleukin-1 beta; Intervention; Knock-out; Knockout Mice; Knowledge; Lead; Ligand Binding; Ligands; Link; Lipids; Longevity; MAP3K7 gene; Macronutrients Nutrition; Metabolic; Metabolic Diseases; Metabolism; Metformin; Mitochondria; Molecular; Mus; NADH; NF-kappa B; Obesity; Pathway interactions; Pharmacology; Phenotype; Phosphotransferases; Process; Protein Kinase; Proteins; Proteomics; Recombinant Proteins; Research; Research Activity; Research Personnel; Resveratrol; Risk Factors; Rodent; SIRT1 gene; STK11 gene; Secure; Sepharose; Signal Transduction; Sirolimus; Small Interfering RNA; Sorting - Cell Movement; Supervision; System; TNF gene; Technical Expertise; Techniques; Testing; Time; Tissues; Training; Transforming Growth Factors; Visceral; Western Blotting; Woman; Work; age related; aged; career development; design; detection of nutrient; enantiomer; follow-up; healthspan; laboratory experience; macrophage; male; member; men; novel; overexpression; receptor; recruit; research and development; young adult

PROJECT SUMMARY/ABSTRACT The research and career development activities outlined in this application have been designed to equip the candidate, Dr. Michael Stout, with the scientific and technical expertise necessary to become an independent investigator. The proposed research aims to elucidate the mechanisms responsible for the alleviation of age- related metabolic and inflammatory dysfunction by 17α-estradiol and identify the receptor(s)/pathway(s) by which these effects occur. As such, the candidate will receive additional training in signaling networks directly relevant to this area of research through intensive coursework and hands-on laboratory experience under the supervision of Drs. James Kirkland, Eduardo Chini, and Sundeep Khosla. The short-term objectives of this application are to enhance the candidate's knowledge of nutrient-sensing and inflammatory pathway interactions and develop technical skills to evaluate these relationships in culture- and animal-model systems. The long-term goals of this application are to enable the candidate, as a newly-hired faculty member, to secure protected time for research activities, establish new collaborations, and develop a novel line of research that produces competitive grant proposals for future funding. Preliminary studies performed by the candidate under the direction of Dr. James Kirkland indicate that 17α-estradiol enhances metabolic function and alleviates inflammation in older mice through pathways that are central to metabolic homeostasis and the aging process. This proposal will expand upon these findings by unraveling the intracellular mechanisms responsible for these phenotypes while also identifying receptor(s)/pathway(s) by which 17α-estradiol elicits these downstream effects. The overall hypothesis is that 17α-estradiol signals through an uncharacterized receptor/pathway leading to activation of AMPK and alleviation of metabolic and inflammatory dysfunction. The candidate will test this hypothesis through the following aims: 1) Determine if metabolic enhancement by 17α-estradiol is AMPK-dependent; 2) Determine if 17α-estradiol reduces inflammation by suppressing mTOR and/or NFKB; and 3) Identify the receptor(s)/pathway(s) by which 17α-estradiol elicits its cellular effects. This work will significantly enhance the understanding of molecular and cellular pathways by which 17α-estradiol elicits its effects which could lead to the development of novel treatments for aging- and/or obesity-related metabolic and inflammatory disorders.

项目总结/摘要 本申请中概述的研究和职业发展活动旨在装备 候选人，迈克尔斯托特博士，具有必要的科学和技术专长，成为一个独立的 调查员这项拟议的研究旨在阐明负责缓解年龄的机制- 17α-雌二醇相关的代谢和炎症功能障碍，并通过 这些影响是如何发生的。因此，候选人将直接接受信令网络方面的额外培训 通过密集的课程作业和动手实验室经验， James柯克兰、Eduardo Chini和Sundeep Khosla博士的监督。短期目标是 应用程序是为了提高候选人的营养感应和炎症途径的知识 互动和发展技术技能，以评估这些关系的文化和动物模型系统。 这个应用程序的长期目标是使候选人，作为一个新雇用的教师，以确保 保护研究活动的时间，建立新的合作，并开发一个新的研究线， 为未来的资金提供有竞争力的赠款提案。候选人在下列条件下进行的初步研究 James柯克兰博士指导表明，17α-雌二醇增强代谢功能并使 通过对代谢稳态和衰老过程至关重要的途径，在老年小鼠中抑制炎症。 这项建议将扩大这些发现，解开细胞内机制负责这些 表型，同时还确定17α-雌二醇激发这些下游的受体/途径 方面的影响.总的假设是17α-雌二醇通过一个未表征的受体/通路进行信号传导 导致AMPK的活化和代谢和炎症功能障碍的减轻。候选人将 通过以下目的来检验这一假设：1）确定17α-雌二醇的代谢增强作用是否 2）确定17α-雌二醇是否通过抑制mTOR和/或NF κ B来减轻炎症; （3）确定17α-雌二醇发挥其细胞效应的受体/途径。这项工作将 显著增强了对17α-雌二醇激发其表达的分子和细胞途径的理解， 可能导致开发用于衰老和/或肥胖相关代谢的新疗法的效果 和炎性疾病。