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.

项目摘要/摘要本应用程序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（Michael Stout）博士，具有成为独立的科学和技术专长研究者。拟议的研究旨在阐明负责减轻年龄的机制。 17α-雌二醇的相关代谢和炎症功能障碍，并通过这些影响发生。因此，候选人将直接接受有关信号网络的额外培训通过密集的课程和实践实验室经验与这一研究领域有关医生的监督。 James Kirkland，Eduardo Chini和Sundeep Khosla。此的短期目标应用是为了增强候选人对营养感和炎症途径的了解互动并发展技术技能，以评估文化和动物模型系统中的这些关系。本申请的长期目标是使候选人成为新租用的教职员工，以确保保护研究活动的时间，建立新的合作并开发一条新颖的研究系列为未来的资金提供竞争性的赠款建议。候选人在詹姆斯·柯克兰（James Kirkland）博士的方向表明17α-雌二醇增强了代谢功能并减轻老鼠的炎症通过代谢稳态和衰老过程的核心途径。该提议将通过揭示负责这些的细胞内机制来扩展这些发现表型同时还识别接收器/途径17α-雌二醇引起这些下游的途径效果。总体假设是17α-雌二醇通过未表征的接收器/途径信号导致AMPK激活以及缓解代谢和炎症功能障碍。候选人会通过以下目的检验该假设：1）确定17α-雌二醇的代谢增强是否为依赖AMPK； 2）确定17α-雌二醇是否通过抑制MTOR和/或NFKB来降低注射； 3）确定17α-雌二醇会引起其细胞效应的接收器/途径。这项工作将显着增强了对分子和细胞途径的理解，17α-雌二醇会引起其可能导致衰老和/或与肥胖相关的代谢的新型治疗方法发展的影响和炎症性疾病。