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: 9977777
• 负责人: Michael B Stout
• 金额: $ 24.84万
• 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/9977777
• 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.

项目摘要/摘要 本申请中概述的研究和职业发展活动旨在为 候选人迈克尔·斯托特博士，拥有成为独立人士所需的科学和技术专长 调查员。这项拟议的研究旨在阐明导致衰老的机制-- 17α-雌二醇引起的相关代谢和炎症功能障碍及其受体(S)/通路(S)的确定 这些影响会发生在哪里。因此，候选人将直接接受信令网络方面的额外培训 通过密集的课程工作和实践实验室经验与这一领域的研究相关 詹姆斯·柯克兰博士、爱德华多·奇尼博士和桑迪普·科斯拉博士的监督。这样做的短期目标是 应用程序是为了增强候选人对营养感官和炎症途径的知识 并开发技术技能，在文化和动物模型系统中评估这些关系。 这项申请的长期目标是使应聘者作为一名新聘用的教职员工，能够确保 保护研究活动的时间，建立新的合作关系，并开发一种新的研究路线 为未来的资金提供有竞争力的赠款建议。候选人在以下情况下进行的初步研究 詹姆斯·柯克兰博士的指导表明，17α-雌二醇增强代谢功能，缓解 老年小鼠的炎症通过代谢动态平衡和衰老过程的中心途径进行。 这项提案将通过解开导致这些发现的细胞内机制来扩展这些发现 同时识别17α-雌二醇引起这些下游的受体(S)/途径(S)的表型 效果。总体假设是17个α-雌二醇通过一种未知的受体/途径发出信号 从而激活AMPK，缓解代谢和炎症功能障碍。候选人将会 通过以下目标验证这一假设：1)确定17α-雌二醇是否促进代谢 2)确定17α-雌二醇是否通过抑制mTOR和/或NFKb而减轻炎症； 3)确定17α-雌二醇的细胞效应的受体(S)/途径(S)。这项工作将 极大地提高了对17α-雌二醇诱导其 可能导致开发治疗衰老和/或肥胖相关代谢的新疗法的效果 和炎症性疾病。