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MiR-21 Exacerbates Cytokine Induced Beta Cell Dysfunction Via Inhibition of mRNAs Regulating Beta Cell Identity

MiR-21 通过抑制调节 β 细胞身份的 mRNA 加剧细胞因子诱导的 β 细胞功能障碍

基本信息

批准号：
9982674
负责人：
Sara Ibrahim
金额：
$ 2.98万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-12 至 2023-07-11
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9982674
关键词：
Address Advisory Committees Affect Animal Model Apoptosis Autoimmunity Award B cell therapy B-Cell Development BCL2 gene Beta Cell Binding Biological Models Biotin Cell Survival Cell physiology Cells Clinical Data Data Set Development Diabetes Mellitus Diet Dose Environment Etiology Exhibits Exposure to FGFR3 gene Family member Functional disorder Funding Genetic Genetic Translation Glucose Glucose Intolerance Goals Grant Heat-Shock Response High Fat Diet Human Hyperglycemia In Vitro Indiana Inflammation Inflammatory Insulin Insulin-Dependent Diabetes Mellitus Knock-out Knowledge Lead Measurement Mentors Messenger RNA Metabolic Diseases Metabolic stress MicroRNAs Modeling Molecular Molecular Biology Mus Non-Insulin-Dependent Diabetes Mellitus Nonesterified Fatty Acids Nuclear Obesity Oral Pathologic Pathway interactions Phenotype Physiological Play Preparation Prevalence Process Research Research Personnel Research Training Role Signal Transduction Small RNA Streptozocin Stress System Techniques Testing Tetanus Helper Peptide Time Training Transfection Transforming Growth Factor Beta 2 Transgenic Animals Transgenic Mice Transgenic Organisms Translational Research United States United States National Institutes of Health Universities Validation Work Zebrafish aldehyde dehydrogenase 1 base blood glucose regulation career cell dedifferentiation cost cytokine design endoplasmic reticulum stress experience experimental study glucose tolerance improved in silico in vivo insulin secretion insulin tolerance islet medical schools member mouse model novel novel therapeutics overexpression prevent promoter response transcriptome sequencing

项目摘要

PROJECT SUMMARY In the United States alone, diabetes affects over 30 million people and costs a staggering $245 billion annually. A hallmark of diabetes is the loss of physical or functional β cell mass. Recent data suggest that the intrinsic β cell response to inflammatory and metabolic stress ultimately impacts β cell function and survival. Aberrant microRNA (miRNA) expression has been demonstrated in the β cell. MiRNAs have also been shown to serve as important regulators of β cell development and function, implicating them in β cell dysfunction during diabetes development. The long-term goal of this applicant is to establish an independent translational research career exploring diabetes pathophysiology as it relates to β cells, and specifically focusing on the role of β cell miRNAs in diabetes development. This application's central hypothesis is that β cell microRNA-21 (miR-21) plays a critical role in inhibiting β cell function and inducing loss of β cell identity. Two specific aims are proposed to test this hypothesis. Experiments in Aim 1 will use an in vitro Tet-on INS1 lentiviral system of dose dependent miR-21 overexpression to carefully validate physiologic effects of increased β cell miR-21 and delineate direct mRNA targets by which miR-21 exerts these effects. Effects on dedifferentiation/plasticity will be further evaluated using lineage tracing in a zebrafish model of miR-21 overexpression. Experiments in Aim 2 will test effects of miR-21 on β cell function and identity in a mammalian system, using genetic mouse models of inducible miR-21 knockout and overexpression. Completion of these aims will, for the first time, define the role of pathologic cytokine- induced increases in β cell miR-21 on β cell function and identity. This F30 award entails a 4-year training plan designed to achieve 4 main objectives: 1) train in state-of-the-art techniques and concepts in diabetes research 2) train in the use of transgenic animal models for diabetes research 3) train in oral and written presentation of research findings, including grant preparation and 4) integrate clinical experiences with research training.The applicant will benefit from the outstanding and collaborative research environment provided by the Center for Diabetes and Metabolic Diseases at the Indiana University School of Medicine. Her training will also benefit from a mentoring and advisory committee consisting of a diverse team of carefully selected and established NIH funded investigators. The proposed training will provide the applicant with a fertile training environment in which she can develop an understanding of β cell physiology and expand her molecular biology toolkit within an existing translational collaborative team.

项目总结