Role of miR-6236 in Obesity-Associated Adipose Tissue Dysfunction

miR-6236 在肥胖相关脂肪组织功能障碍中的作用

基本信息

批准号：
10282575
负责人：
David Andrew Hill
金额：
$ 13.2万
依托单位：
CHILDREN'S HOSP OF PHILADELPHIA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10282575
关键词：
Adipocytes Adipose tissue Adult Advisory Committees Applications Grants Award Biology Body Composition Cardiovascular Diseases Cell Respiration Cell physiology Cells Data Diabetes Mellitus Energy Intake Energy Metabolism Environment Flow Cytometry Foundations Functional disorder Funding Future Gene Expression Generations Genetic Transcription Goals HIV Health Homeostasis Human Hypertrophy Immune Immunobiology Immunohistochemistry Immunologics Impairment In Vitro Inflammatory Insulin Resistance Knockout Mice Lipids Malignant Neoplasms Manuscripts Measures Mediating Mentorship Metabolic Metabolic dysfunction Metabolism MicroRNAs Mitochondria Molecular Morbidity - disease rate Mouse Strains Mus Myelogenous Obese Mice Obesity Outcome Overweight Paper Pathway interactions Pattern Pediatric Hospitals Pennsylvania Phenotype Philadelphia Postdoctoral Fellow Preparation Prevalence Production Publications Publishing Research Respiration Role Site System Testing Therapeutic Thinness Time Tissues Transgenic Mice Tumor-infiltrating immune cells United States National Institutes of Health Universities Weight Gain Whole Organism Work adipocyte biology base blood glucose regulation career development cell type cytokine extracellular vesicles graduate student in vitro Model in vivo innovation loss of function macrophage member mortality mouse model novel novel therapeutics obesity treatment pandemic disease preservation programs stem symposium tenure track transcriptome transcriptome sequencing uptake

Adipocytes Adipose tissue Adult Advisory Committees Applications Grants Award Biology Body Composition Cardiovascular Diseases Cell Respiration Cell physiology Cells Data Diabetes Mellitus Energy Intake Energy Metabolism Environment Flow Cytometry Foundations Functional disorder Funding Future Gene Expression Generations Genetic Transcription Goals HIV Health Homeostasis Human Hypertrophy Immune Immunobiology Immunohistochemistry Immunologics Impairment In Vitro Inflammatory Insulin Resistance Knockout Mice Lipids Malignant Neoplasms Manuscripts Measures Mediating Mentorship Metabolic Metabolic dysfunction Metabolism MicroRNAs Mitochondria Molecular Morbidity - disease rate Mouse Strains Mus Myelogenous Obese Mice Obesity Outcome Overweight Paper Pathway interactions Pattern Pediatric Hospitals Pennsylvania Phenotype Philadelphia Postdoctoral Fellow Preparation Prevalence Production Publications Publishing Research Respiration Role Site System Testing Therapeutic Thinness Time Tissues Transgenic Mice Tumor-infiltrating immune cells United States National Institutes of Health Universities Weight Gain Whole Organism Work adipocyte biology base blood glucose regulation career development cell type cytokine extracellular vesicles graduate student in vitro Model in vivo innovation loss of function macrophage member mortality mouse model novel novel therapeutics obesity treatment pandemic disease preservation programs stem symposium tenure track transcriptome transcriptome sequencing uptake

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项目摘要

PROJECT SUMMARY/ABSTRACT This proposed two-year project stems directly from studies and career development activities related to my current K08 (DK116668), and represents a new research direction that will enhance my advancement towards independence through the generation of preliminary data and publications to support an R01-level application on how adipose tissue macrophages (ATMs) influence adipose tissue homeostasis and organismal metabolism. During the first two years of my K08 award I published multiple papers, obtained a tenure-track assistant professorship at the University of Pennsylvania (Penn), and initiated my independent research program at Children’s Hospital of Philadelphia (CHOP). With the continued mentorship of Dr. Mitchell Lazar and my K08 advisory committee, my independent research lab has grown dramatically in its first year and now numbers six full-time research staff, graduate students, and post-docs. I have obtained independent foundation support for my lab, and an NIH supplement to study the role of ATMs in HIV-associated metabolic dysfunction. We have published our first fully-independent (senior author) research manuscripts, and I have been invited to speak at multiple national conferences. My lab is now ready to accelerate our research program in ATMs in preparation for the transition to R01 funding. My R03 proposal focuses on understanding how a novel, ATM-secreted microRNA (miR-6236) influences adipocyte functions and organismal metabolism in the context of obesity. miR-6236 is both a novel miRNA, and the most highly expressed and highly secreted ATM miRNA. To facilitate our studies of this molecule, we have developed two novel transgenic mouse models that allow for whole organism or tissue-specific loss-of-function of miR-6236 in vivo. Whole body deletion of miR-6236 leads to increased weight gain, and impaired glucose control in the context of obesity. We have also developed in vitro models that preliminarily suggest that miR- 6236 controls mitochondrial respiration in adipocytes. Together, these data support our primary hypothesis that miR-6236 protects against obesity and it’s sequela by influencing how ATMs function in, and interact with, their tissue environment. We will test this hypothesis by crossing an established miR-6236 LoxP mouse line to the LysM-Cre most strain, effectively deleting miR-6236 in the myeloid immune lineages. The goal of this proposal is to comprehensively phenotype the effects of myeloid-specific miR-6236 deficiency on the adipose tissue macrophages, adipocytes, and mammalian metabolism. This work is a natural extension of my K08, and will act as a paradigm for future studies of ATM-secreted miRNAs in my lab. Importantly, this proposal will support the generation of publications and preliminary data for an R01-level application in this field.

项目摘要/摘要这是从与我的研究和职业发展活动直接提出的为期两年的项目步骤当前的K08（DK116668），代表了一个新的研究方向，将增强我的进步通过生成初步数据和出版物来支持R01级应用程序的独立性关于脂肪组织巨噬细胞（ATM）如何影响脂肪组织稳态和有机代谢。在我的K08奖的头两年中，我发表了多篇论文，获得了终身助手宾夕法尼亚大学（宾夕法尼亚大学）的教授，并启动了我的独立研究计划费城儿童医院（CHOP）。米切尔·拉扎尔（Mitchell Lazar）和我的K08的持续心态咨询委员会，我的独立研究实验室在第一年就显着增长，现在有六个全日制研究人员，研究生和毕业后。我已经获得了独立的基础支持我的实验室以及NIH的补充，用于研究ATM在与HIV相关的代谢功能障碍中的作用。我们有出版了我们的第一个完全独立的（高级作者）研究手稿，并被邀请在多次民族会议。我的实验室现在准备加速我们在ATM中进行的研究计划过渡到R01资金。我的R03提案重点是了解新颖的ATM分泌MicroRNA（miR-6236）如何影响在肥胖的背景下，脂肪细胞功能和有机代谢。 miR-6236既是新颖的miRNA，又最高表达和高度分泌的ATM miRNA。为了促进我们对该分子的研究，我们有开发了两个新型的转基因小鼠模型，可允许整个生物体或组织特异性功能丧失 Mir-6236体内。 miR-6236的全身缺失导致体重增加增加，葡萄糖受损在肥胖的背景下进行控制。我们还开发了体外模型，这些模型初步表明mir- 6236控制脂肪细胞中的线粒体呼吸。这些数据共同支持我们的主要假设 miR-6236可以通过影响ATM的功能和与之相互作用的影响来防止肥胖症及其续集组织环境。我们将通过将已建立的miR-6236 LOXP小鼠线跨到该假设来检验这一假设 Lysm-Cre最大菌株，有效地删除了髓样免疫谱系中的miR-6236。该提议的目标是为了全面表型，髓样特异性miR-6236缺乏对脂肪组织的影响巨噬细胞，脂肪细胞和哺乳动物代谢。这项工作是我K08的自然延伸，将行动作为我实验室中ATM分泌的miRNA的未来研究的范式。重要的是，该建议将支持在该领域的R01级应用程序的生成出版物和初步数据。