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

描述(申请人提供)：肥胖是胰岛素抵抗相关疾病的主要病理基础，如2型糖尿病。我们和其他人之前已经证明，内质网(ER)应激在肥胖条件下增加，并在胰岛素抵抗的发展中发挥核心作用。最近，我们发现XBP1s(X-box结合蛋白的剪接形式)是肥胖状态下内质网应激和胰岛素抵抗的关键调节因子，它与磷脂酰肌醇3-激酶(PI3K)、P85和P85的调节亚基相互作用。 P85？是其功能的关键。我们进一步证明，在肥胖中，XBP1s不与P85s相互作用，导致XBP1s核转位严重缺陷，这一病理在肥胖症中内质网应激的发生以及随后的胰岛素抵抗和2型糖尿病的发生中起着至关重要的作用。我最近发现了另一种XBP1s调节蛋白，它增加了XBP1s的核转位。我的建议建立在这些新发现的基础上，旨在调查新发现的XBP1s调节因子在内质网应激、胰岛素抵抗和肥胖中的作用。通过在体外和体内使用获得和损失函数的方法，我建议研究该蛋白在内质网应激、糖耐量异常和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，并期待在调节胰岛素抵抗和内质网压力方面发现一种新的机制。我的主要职业目标是成为一名国际公认的研究学者，并建立一个强大的项目，致力于了解肥胖相关病理和2型糖尿病的分子机制，并制定此类疾病的治疗策略。我的直接职业目标是对该领域有更好的了解，并学会作为一名独立教员管理实验室。初级和顾问共同指导，包括研讨会和课程、科学会议和讲座的培训计划，以及会议是我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；提高解释数据的技能；克服必要的实验障碍，提高写作技巧。我还将受益于奥兹坎博士在内质网压力和肥胖领域的专业知识，以及坎特利博士，他是PI3K领域的世界领先科学家。在教师培训计划中，我将建立一个资源网络，获得有关资助机会的信息，学习撰写补助金，并通过提高指导能力和认识到可预见的挑战，为自己成为一名独立科学家做好准备。通过会议、研讨会和会议，我将了解其他人是如何执行他们的想法和设定他们的假设的，并提高我的演讲技巧。我所拥有最优秀和最具启发性的环境，可以在地理位置、协作、设施以及与其他科学家的互动等多个方面进行研究。我们的实验室在应激、UPR、肥胖和2型糖尿病领域建立得很好，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一种治疗2型糖尿病的新方法。

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.