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

• 批准号: 8384040
• 负责人: Sang Won Park
• 金额: $ 9万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8384040
• 关键词: Achievement; Address; Adenoviruses; Binding Proteins; Blood Glucose; Boxing; Bromodomain; Cell Nucleus; Cells; Chronic; Collaborations; Data; Defect; Development; Development Plans; Diabetes Mellitus; Diabetic mouse; Diet; Disease; Drug Delivery Systems; Endoplasmic Reticulum; Environment; Enzymes; Faculty; Fatty acid glycerol esters; Funding Opportunities; Future; Gene Silencing; Glucose; Glucose Intolerance; Goals; Grant; Homeostasis; Hormones; In Vitro; Institutes; Insulin; Insulin Resistance; Laboratories; Lead; Learning; Liver; Location; Maintenance; Mediating; 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; Stress; Techniques; Therapeutic; Thinking; Training Programs; Transgenic Mice; Tumor Suppressor Proteins; Writing; base; blood glucose regulation; career; career development; coping; design; diabetic; endoplasmic reticulum stress; feeding; gain of function; glucose tolerance; improved; in vivo; insulin sensitivity; interest; lectures; loss of function; meetings; member; mouse model; novel; novel therapeutic intervention; novel therapeutics; overexpression; programs; protein folding; research study; response; skills; small hairpin RNA; symposium; transcription factor; treatment strategy

DESCRIPTION (provided by applicant): 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 ofER 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. PUBLIC HEALTH RELEVANCE: One of the most serious complications of obesity is the condition where the body becomes insensitive to a hormone called insulin (insulin resistance), which is a major cause for the development of type 2 diabetes (a condition characterized by high blood sugar levels and insulin resistance). In recent years, we have identified a new mechanism involving endoplasmic reticulum (ER) stress as a crucial factor for development of insulin resistance and type 2 diabetes in obesity. The aims of my proposal are to further investigate the molecular mechanism and develop a new drug target for treatment of insulin resistance and type 2 diabetes.

描述（由申请人提供）：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）应激在肥胖状态下增加，它在胰岛素抵抗的发展中起着核心作用。最近，我们确定了XBP 1（X-box结合蛋白的剪接形式）作为肥胖条件下ER应激和胰岛素抵抗的关键调节因子，并且其与磷脂酰肌醇3激酶（PI 3 K）、p85和 第85章对她的作用至关重要我们进一步证明，肥胖症中的XBP 1 s不与p85相互作用，导致XBP 1 s核转位的严重缺陷，这种病理学在ER应激和随后的胰岛素抵抗和肥胖症中的2型糖尿病的发展中起着至关重要的作用。我最近发现了另一种XBP 1 s调节蛋白，它增加了XBP 1 s的核转位。我的建议是建立在这些新发现的基础上，旨在研究新发现的XBP 1 s调节剂在ER应激，胰岛素抵抗和肥胖中的作用。通过在体外和体内使用增益和损失功能的方法，我建议调查这种蛋白质在ER应激，葡萄糖耐受不良和2型糖尿病的发展中的作用。我最近的新发现鼓舞了我，并期望在胰岛素抵抗和ER应激的调节中发现一种新的机制。我的主要职业目标是成为一名国际公认的研究学者，并建立一个强大的计划，致力于了解肥胖相关病理和2型糖尿病的分子机制，并制定治疗此类疾病的策略。我的近期职业目标是更好地了解这些领域，并学会作为独立的教师管理实验室。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Ozcan博士在ER压力和肥胖领域的专业知识以及Cantley博士，他是PI 3 K领域的世界领先科学家。在教师培训计划中，我将开发一个资源网络，获得有关资助机会的信息，学习撰写赠款，并通过提高导师能力和认识可预测的挑战，使自己成为一名独立的科学家。通过会议，研讨会和会议，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。我的研究所在许多方面都有最优秀和最刺激的环境来进行研究，例如位置，合作，设施以及与其他科学家的互动。我们的实验室在ER应激，UPR，肥胖和2型糖尿病领域建立良好，并配备了本提案中设计的实验所需的所有必要试剂和技术技能。正如我最近的成就所证明的那样，我相信我已经将自己定位为一名成功的独立研究者，我希望在不久的将来将我的研究从了解基本机制扩展到开发治疗2型糖尿病的新治疗方法。 公共卫生关系：肥胖症最严重的并发症之一是身体对称为胰岛素的激素不敏感（胰岛素抵抗）的情况，这是2型糖尿病（以高血糖水平和胰岛素抵抗为特征的情况）发展的主要原因。近年来，我们已经确定了一个新的机制，涉及内质网（ER）应激作为一个关键因素的发展胰岛素抵抗和2型糖尿病的肥胖。本课题的目的是进一步研究胰岛素抵抗和2型糖尿病的分子机制，并为胰岛素抵抗和2型糖尿病的治疗提供新的药物靶点。