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: 8785168
• 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
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-16 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8785168
• 关键词: Achievement; Address; Adenoviruses; Binding Proteins; Blood Glucose; Boxing; Bromodomain; Cell Nucleus; Cells; Chronic; Collaborations; Critical Thinking; Data; Defect; Development; Development Plans; Diabetes Mellitus; Diabetic mouse; Diet; Disease; Drug Targeting; 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; Teacher Professional Development; Techniques; Therapeutic; 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

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.

项目总结