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：
10441535
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/10441535
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

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.

项目概要/摘要这个拟议的两年项目直接源于与我相关的研究和职业发展活动目前的 K08 (DK116668)，代表了一个新的研究方向，将促进我在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体代谢。在获得 K08 奖项的前两年，我发表了多篇论文，获得了终身教职助理职位宾夕法尼亚大学 (Penn) 的教授职位，并在在 Mitchell Lazar 博士和我的 K08 的持续指导下，费城儿童医院 (CHOP) 咨询委员会，我的独立研究实验室在第一年就取得了巨大的发展，现在排名第六我获得了全职研究人员、研究生和博士后的独立基金会支持。我的实验室和 NIH 补充品，用于研究 ATM 在 HIV 相关代谢功能障碍中的作用。发表了我们第一篇完全独立（资深作者）的研究手稿，并受邀在我的实验室现在已准备好加速我们在 ATM 方面的研究计划。过渡到 R01 资金。我的 R03 提案侧重于了解 ATM 分泌的新型 microRNA (miR-6236) 如何影响肥胖背景下的脂肪细胞功能和生物代谢。miR-6236 既是一种新型 miRNA，又是一种新的 miRNA。为了促进我们对该分子的研究，我们有最高表达和高度分泌的 ATM miRNA。开发了两种新型转基因小鼠模型，允许整个有机体或组织特异性功能丧失体内 miR-6236 的全身缺失会导致体重增加和血糖受损。我们还开发了体外模型，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 通过影响 ATM 的功能以及与其相互作用来预防肥胖及其后遗症我们将通过将已建立的 miR-6236 LoxP 小鼠品系与 LysM-Cre大多数菌株，有效删除骨髓免疫谱系中的miR-6236，这是该提案的目标。是为了全面表型骨髓特异性 miR-6236 缺陷对脂肪组织的影响巨噬细胞、脂肪细胞和哺乳动物新陈代谢。这项工作是我的 K08 的自然延伸，并将发挥作用。作为我实验室未来 ATM 分泌 miRNA 研究的范例，重要的是，该提案将支持生成该领域 R01 级应用的出版物和初步数据。