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The role of BRD7 in the regulation of endoplasmic reticulum and glucose homeostas

BRD7在内质网和葡萄糖稳态调节中的作用

基本信息

批准号：
9132790
负责人：
Sang Won Park
金额：
$ 24.9万
依托单位：
BOSTON CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-16 至 2018-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9132790
关键词：
Achievement Address Adenoviruses Binding Proteins Blood Glucose Boxing Bromodomain Cell Nucleus Cells Chronic Collaborations Critical Thinking Data Data Analyses Defect Development Development Plans Diabetes Mellitus Diabetic mouse Disease Endoplasmic Reticulum Environment Enzymes Faculty Funding Opportunities Future Gene Silencing Glucose Glucose Intolerance Goals Grant High Fat Diet Homeostasis Hormones In Vitro Institutes Insulin Insulin Resistance Laboratories Lead Learning Liver Location Maintenance Medicine Mentors Mentorship Mitotic Cell Cycle Modeling Molecular Molecular Chaperones Mus Nature Non-Insulin-Dependent Diabetes Mellitus Nuclear Translocation Obese Mice Obesity Organism Pathology Phosphotransferases Play Positioning Attribute Process Proteins RNA Splicing Reagent Regulation Research Research Personnel Resistance Resources Role Scientist Signal Transduction Teacher Professional Development Technical Expertise Techniques Therapeutic Training Programs Transgenic Mice Tumor Suppressor Proteins Writing adenoviral-mediated base blood glucose regulation career career development coping design diabetic endoplasmic reticulum stress feeding field study gain of function glucose tolerance improved in vivo insulin sensitivity interest lectures loss of function meetings member mouse model new therapeutic target novel novel therapeutic intervention novel therapeutics overexpression programs protein folding research study response skills small hairpin RNA symposium transcription factor treatment strategy

项目摘要

PROJECT SUMMARY Obesity is a major pathology underlying insulin resistance related diseases such as type 2 diabetes. We and others have previously shown that endoplasmic reticulum (ER) stress is increased in obesity condition and it plays a central role in the development of insulin resistance. Recently, we identified XBP1s (the spliced form of X-box binding protein) as a key regulator of ER stress and insulin resistance in obesity condition and that its interaction with the regulatory subunits of phosphatidyl-inositol3-kinase (PI3K), p85� and p85�, is crucial for its function. We further documented that XBP1s does not interact with p85s in obesity, resulting in a severe defect in XBP1s nuclear translocation and this pathology plays a crucial role for the development of ER stress and consequent insulin resistance and type 2 diabetes in obesity. I have recently identified another XBP1s regulating protein, which increases XBP1s nuclear translocation. My proposal is built on these novel findings and aims to investigate the role of newly identified XBP1s regulator in ER stress, insulin resistance, and obesity. By using gain and loss function approaches in both in vitro and in vivo, I propose to investigate the role of this protein in the development of ER stress, glucose intolerance, and type 2 diabetes. I am encouraged by my new recent findings and expect to discover a novel mechanism in the regulation of insulin resistance and ER stress. My major career goal is to become an internationally recognized research scholar and establish a strong program dedicated to understanding molecular mechanisms of obesity related pathologies and type 2 diabetes and development of strategy for the treatment of such diseases. My immediate career goal is to have a better understanding in the fields and learn to manage a laboratory as an independent faculty member. Primary and advisory co-mentorship, training programs including seminars and classes, scientific meetings and lectures, and conferences are part of my research career development plan. With support of my mentors, I will improve critical thinking and analysis; advance skills in interpretation of data; overcome necessary experimental obstacles, and improve writing techniques. I will also benefit from Dr. Ozcan's expertise in the fields of ER stress and obesity and Dr. Cantley, who is a world-leading scientist in the field of PI3K. In faculty training programs, I will develop a network of resources, obtain information about funding opportunities, learn to write grants, and prepare myself to be an independent scientist by improving mentorship capability and recognizing predictable challenges. Through meetings, seminars, and conferences, I will learn how other people execute their ideas and set their hypotheses and improve my presentation skills. My institute has the most outstanding and stimulating environment to perform research in many aspects, such as location, collaboration, facility, and interaction with other scientist. Our laboratory is well established in the fields of ER stress, UPR, obesity, and type 2 diabetes and is equipped with all the necessary reagents and technical skills required for the designed experiments in this proposal. As proven by my recent achievements, I believe that I have positioned myself to develop towards a successful independent investigator and I hope to extend my research from understanding the basic mechanisms to development of a new therapeutic approach for the treatment of type 2 diabetes in near future.

项目摘要肥胖是胰岛素抵抗相关疾病如2型糖尿病的主要病理基础。我们和其他人先前已经表明，内质网（ER）应激在肥胖状况下增加，在胰岛素抵抗的发展中起着核心作用。最近，我们发现了XBP 1（ X-box结合蛋白）作为肥胖状况中ER应激和胰岛素抵抗的关键调节因子，与磷脂酰肌醇3-激酶（PI 3 K）的调节亚基p85 β和p85 β的相互作用，对于其功能我们进一步证实，肥胖症中的XBP 1与p85不相互作用，导致严重的缺陷，在XBP 1 s核转位中，这种病理学对ER应激的发展起着至关重要的作用，胰岛素抵抗和2型糖尿病。我最近发现了另一个XBP 1 调节蛋白，其增加XBP 1 s核转位。我的建议是建立在这些新发现之上的旨在研究新发现的XBP 1 s调节剂在ER应激、胰岛素抵抗和胰岛素抵抗中的作用。肥胖通过在体外和体内使用增益和损失函数的方法，我建议调查的作用，这种蛋白质在ER应激、葡萄糖耐受不良和2型糖尿病的发展中的作用。我对我最近的新发现感到鼓舞，并期望发现一种新的调节机制胰岛素抵抗和ER应激。我的主要职业目标是成为国际公认的研究学者和建立一个强大的计划，致力于了解肥胖相关的分子机制病理学和2型糖尿病以及治疗这些疾病的策略的发展。我近期的职业目标是更好地了解这些领域，并学会管理实验室，独立教师。主要和咨询共同指导，培训计划，包括研讨会和课程，科学会议和讲座，以及会议是我的研究职业发展计划的一部分。在导师的支持下，我将提高批判性思维和分析能力;提高数据解释技能; 克服必要的实验障碍，提高写作技巧。我也将受益于博士。 Ozcan在ER压力和肥胖领域的专业知识和Cantley博士，谁是世界领先的科学家，关于PI 3 K在教师培训项目中，我将开发一个资源网络，获取有关资助的机会，学会写赠款，并准备自己是一个独立的科学家，通过提高指导能力和认识到可预见的挑战。通过会议、研讨会和大会，我我将学习其他人如何执行他们的想法和设定他们的假设，并提高我的演讲技巧。我的研究所有最优秀和最刺激的环境，在许多方面进行研究，如位置、协作、设施以及与其他科学家的互动。我们的实验室在世界上有很好的声誉。 ER应激，UPR，肥胖和2型糖尿病领域，并配备了所有必要的试剂和本提案中设计的实验所需的技术技能。从我最近的成就来看，我我相信，我已经定位自己发展成为一个成功的独立调查员，我希望将我的研究从理解基本机制扩展到开发新的治疗方法 2型糖尿病的治疗方法