Role of LncRNAs in diabetic livers

LncRNA 在糖尿病肝脏中的作用

• 批准号: 8868311
• 负责人: AMY Y LEUNG
• 金额: $ 15.51万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2018-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8868311
• 关键词: Affect; Affinity; Animal Model; Applications Grants; Atherosclerosis; Award; Biological Assay; Biological Process; Cardiovascular Diseases; Cell Line; Cells; Chromatin; Chromatin Structure; Clinical; Code; Complex; Data; Development; Diabetes Mellitus; Diabetic Nephropathy; Diabetic mouse; Diet; Disease; Educational process of instructing; Educational workshop; Enhancers; Epidemic; Fatty acid glycerol esters; Funding; Future; Gene Expression; Gene Expression Profile; Gene Targeting; Genes; Genetic; Genetic Models; Gluconeogenesis; Glucose; Goals; Grant; Healthcare Systems; Hepatic; Hepatocyte; Human; Hyperglycemia; Immunoprecipitation; In Vitro; Incidence; Individual; Insulin; Insulin Resistance; Insulin Signaling Pathway; K-Series Research Career Programs; Kidney Diseases; Knowledge; Laboratories; Liver; Mediator of activation protein; Medical; Mentors; Metabolism; Methods; Modeling; Molecular; Molecular Biology; Mus; Neuropathy; Non-Insulin-Dependent Diabetes Mellitus; Overnutrition; Pathogenesis; Pathway interactions; Physiological; Physiology; Population; Process; Proteins; RNA; RNA Sequences; Regulation; Regulator Genes; Regulatory Element; Reporter; Research; Research Activity; Research Personnel; Research Training; Role; Scientist; Severities; Small Interfering RNA; Structure; System; Testing; Training; Training Activity; Training Programs; Transcript; Untranslated RNA; Writing; base; blood glucose regulation; career; career development; chromatin protein; diabetic; differential expression; effective therapy; experience; feeding; genome-wide; glucose production; hepatoma cell; improved; in vivo; innovation; insight; insulin sensitivity; insulin signaling; mouse model; new therapeutic target; non-genetic; novel; novel strategies; overexpression; public health relevance; sedentary lifestyle; skills; success; therapeutic target; transcriptome sequencing

 DESCRIPTION (provided by applicant): Type 2 diabetes (T2D) is already placing a major burden on the US healthcare system and projections indicate the problem will get worse. It is therefore of great importance to further our understanding of the molecular mechanisms that contribute to the onset and establishment of T2D and its complications. This application proposes research and training plans for Dr. Leung to become a leading independent investigator in the field of diabetes. While the applicant has had extensive training in molecular biology and simple model organisms, her development and future success as an investigator will require additional practical skills and knowledge regarding advanced mouse models, mouse physiology and metabolism. To attain the necessary skills and knowledge, she has assembled a strong mentoring team comprising of a group of expert senior investigators and proposed a detailed list of career development and training activities. The mentors: Drs. Natarajan, Tontonoz, Rossi, and Lusis, represent a diverse set of investigators with a track record of successful mentoring and diabetes related research. They will provide guidance and assistance with Dr. Leung's research and training in the development of Dr. Leung's academic career as she transitions to an independently funded investigator. Over the course of this award, she will also engage in additional training activities including structured postgraduate courses intended to increase knowledge and skills in mouse metabolism and physiology, grant-writing workshops, laboratory management workshops, and teaching. The research activities proposed in this application will investigate the role of long non-coding RNAs (lncRNAs) in the development of insulin resistance, dysregulation of gluconeogenesis, and ultimately, T2D. This project is based on extensive preliminary data demonstrating that specific lncRNAs are dysregulated in livers of insulin resistant mice. The overarching hypothesis of this application is that lncRNAs are involved in modulating key genes that regulate insulin signaling pathways and hepatic glucose production, and that dysregulation of these lncRNAs can contribute to the development of insulin resistance and dysregulation of hepatic glucose production. The Specific Aims are: 1) to identify lncRNAs that are dysregulated in livers of diabetic mice, including both genetic and non-genetic mouse models, 2) to determine the functional consequences of altered expression of lncRNAs in the livers of diabetic mice, and 3) to characterize the mechanism of action and regulation of candidate lncRNAs in livers under diabetic conditions. The results from the proposed studies will provide significant new insights into the molecular mechanisms that accompany the development of hepatic insulin resistance and T2D and will form the basis of future grant applications from the applicant. This project will furthermore provide Dr. Leung with the necessary experience for her development into an independent scientist.

 描述（由申请人提供）：2型糖尿病（T2D）已经给美国医疗保健系统带来了重大负担，预测表明该问题将变得更糟。因此，进一步了解T2D及其并发症的发病和建立的分子机制非常重要。本申请为梁博士提供研究和培训计划，使其成为糖尿病领域领先的独立研究者。虽然申请人在分子生物学和简单的模型生物体方面接受了广泛的培训，但她作为研究者的发展和未来的成功将需要有关高级小鼠模型，小鼠生理学和代谢的额外实践技能和知识。为了获得必要的技能和知识，她组建了一个由资深调查员专家组成的强大的辅导小组，并提出了一份职业发展和培训活动的详细清单。导师们：Natarajan，Tontonoz，Rossi和Lusis博士代表了一系列不同的研究人员，他们在成功的指导和糖尿病相关研究方面有着良好的记录。他们将为梁博士的研究和培训提供指导和帮助，帮助梁博士过渡到独立资助的研究人员。在这个奖项的过程中，她还将从事额外的培训活动，包括结构化的研究生课程，旨在增加知识和技能，小鼠代谢和生理学，赠款写作研讨会，实验室管理研讨会和教学。本申请中提出的研究活动将研究长链非编码RNA（lncRNA）在胰岛素抵抗、胰岛素生成失调和最终T2D发展中的作用。该项目基于大量的初步数据，这些数据表明特定的lncRNA在胰岛素抵抗小鼠的肝脏中失调。本申请的首要假设是lncRNA参与调节调节胰岛素信号传导途径和肝葡萄糖产生的关键基因，并且这些lncRNA的失调可促成胰岛素抵抗的发展和肝葡萄糖产生的失调。具体目标是：1）鉴定糖尿病小鼠肝脏中失调的lncRNA，包括遗传和非遗传小鼠模型，2）确定糖尿病小鼠肝脏中lncRNA表达改变的功能后果，和3）表征糖尿病条件下肝脏中候选lncRNA的作用和调节机制。拟议研究的结果将为伴随肝脏胰岛素抵抗和T2D发展的分子机制提供重要的新见解，并将成为申请人未来拨款申请的基础。这个项目将进一步为梁博士提供必要的经验，使她成为一名独立的科学家。