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

项目总结 肥胖是2型糖尿病等胰岛素抵抗相关疾病的主要病理基础。我们和 此前已有研究表明，肥胖状态下内质网(ER)压力会增加，而且 在胰岛素抵抗的发展中起着核心作用。最近，我们发现了XBP1(拼接形式的 X-box结合蛋白)作为肥胖状态下内质网应激和胰岛素抵抗的关键调节因子，其 与磷脂酰肌醇3-激酶(PI3K)调节亚基P85和P85的相互作用对其 功能。我们进一步证明，在肥胖中，XBP 1不与P85相互作用，导致严重缺陷 在XBP1的核转位中，这种病理在内质网应激和内质网的发展中起着至关重要的作用 肥胖导致的胰岛素抵抗和2型糖尿病。我最近又发现了另一个XBP1 调节蛋白质，增加XBP1s的核转位。我的建议是建立在这些新发现的基础上的 并旨在研究新发现的XBP1s调节因子在内质网应激、胰岛素抵抗和 肥胖。通过在体外和体内使用获得和损失函数的方法，我建议研究这种作用 这种蛋白在内质网应激、糖耐量减低和2型糖尿病的发生中起重要作用。 我对我最近的新发现感到鼓舞，并期待发现一种新的机制来调节 胰岛素抵抗和内质网应激。我的主要职业目标是成为国际公认的研究人员 学者并建立了一个致力于了解肥胖相关分子机制的强大计划 病理学和2型糖尿病以及治疗这类疾病的策略的制定。我的 目前的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。初级和咨询共同指导、培训方案，包括研讨会和 课程、科学会议、讲座和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。我也将从Dr。 Ozcan在内质网应激和肥胖领域的专业知识，以及坎特利博士，他是 PI3K领域。在师资培训项目中，我将开发网络资源，获取有关信息 资助机会，学习写资助，并通过改进使自己准备成为一名独立的科学家 指导能力和认识到可预见的挑战。通过会议、研讨会和会议，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，并提高我的演示技能。 我所拥有最优秀和最鼓舞人心的环境来进行多方面的研究，如 作为位置、协作、设施以及与其他科学家的互动。我们的实验室建在世界上 内质网应激、UPR、肥胖和2型糖尿病领域，并配备了所有必要的试剂和 本建议书中设计的实验所需的技术技能。正如我最近取得的成就所证明的那样，我 我相信我已经将自己定位为一名成功的独立调查员，我希望 将我的研究从了解基本机制扩展到开发新的治疗方法 在不久的将来用于治疗2型糖尿病。

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.