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

基本信息

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
项目类别：
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&apos -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

项目摘要

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.

项目概要/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 (Michael Stout) 博士拥有成为独立科学家所需的科学和技术专业知识研究者提出的研究旨在阐明缓解年龄增长的机制。 17α-雌二醇相关的代谢和炎症功能障碍，并通过以下方式识别受体/途径因此，候选人将直接接受信号网络方面的额外培训。通过强化课程和实验室实践经验与该研究领域相关 James Kirkland 博士、Eduardo Chini 博士和 Sundeep Khosla 博士的监督。应用程序旨在增强候选人对营养感应和炎症途径的了解相互作用并发展技术技能来评估文化和动物模型系统中的这些关系。此应用程序的长期目标是使候选人作为新聘用的教员能够确保保护研究活动的时间，建立新的合作，并开发新颖的研究路线为候选人在未来的资助下进行的初步研究提出竞争性的资助提案。 James Kirkland博士的指导表明17α-雌二醇增强代谢功能并缓解老年小鼠的炎症通过代谢稳态和衰老过程的核心途径发生。该提案将通过阐明负责这些的细胞内机制来扩展这些发现表型，同时还识别 17α-雌二醇引发这些下游的受体/途径总体假设是 17α-雌二醇通过未表征的受体/途径发出信号。导致 AMPK 的激活并缓解代谢和炎症功能障碍。通过以下目标检验该假设： 1) 确定 17α-雌二醇促进代谢是否有效 AMPK 依赖性；2) 确定 17α-雌二醇炎症是否通过抑制 mTOR 和/或 NFKB 来减轻； 3) 确定 17α-雌二醇引发其细胞效应的受体/途径。显着增强对 17α-雌二醇引发其作用的分子和细胞途径的理解可能导致针对衰老和/或肥胖相关代谢的新疗法的开发和炎症性疾病。