Regulation of Inflammation and Atherosclerosis by TCF21

项目总结 这份为期五年的K08计划将为候选人Juyong Brian Kim提供严格的培训，以满足特定的要求 在研究和专业发展方面的需求，并成功推出了他的独立医生-科学家 职业生涯。长期目标是为候选人的终身职业生涯做好准备，成为一名专注于内科医生和科学家的人 并最终改善对动脉粥样硬化患者的管理 开发新的治疗方法。 候选人的主要导师是托马斯·奎特莫斯博士，他是一位享誉国际的 高通量遗传学、转录调控机制和血管生物学。候选人也是 在一个在血管生物学和疾病方面拥有专业知识的顾问和合作者委员会的支持下， 表观遗传学和基因组学(威廉·格林利夫博士、加里·欧文斯博士、玛琳·拉比诺维奇博士、菲尔·曹博士和肖恩博士) Wu)。候选人、导师和咨询委员会共同制定了职业发展计划 这将：i)培养候选人在以下重要领域成功研究的科学背景 与他的临床兴趣相一致；ii)促进应聘者获得新的细胞和 分子生物学和遗传学；以及三)在博士后培训和 独立调查。培训计划包括专门的研究时间、出席会议以 介绍原创工作、领导力发展、出席学术研讨会、讲座和期刊俱乐部， 与指导和咨询委员会举行正式和非正式会议，以及在 负责任的研究行为。所有关键人员在指导学员方面都有丰富的经验。 此外，斯坦福大学致力于为 应聘者的职业发展。候选人将拥有所有资源、基础设施和支持，以 确保成功。应聘者拥有新装修和设备齐全的实验室空间，并得到 临床同事和支持人员，确保至少80%的时间用于研究和 支持通过医学院提供的大量核心设施和共享资源 通过导师和咨询委员会的实验室。斯坦福大学提供了理想的 为求职者的职业发展创造良好的环境。 这一提议的研究主题通过确定一部小说来填补该领域的重大知识空白 动脉粥样硬化病变中导致平滑肌细胞炎症和斑块不稳定的机制。 动脉粥样硬化是一种基因复杂的特征，它夺走的生命比癌症、肺部疾病和事故更多 加在一起。候选人提出了几种假设驱动的方法，这些方法将解决 了解动脉粥样硬化的遗传基础。在具体目标1中，候选人将定义 TCF21基因对冠状动脉平滑肌细胞炎症表型影响的初步研究 TCF21调节促炎网络的研究结果。他还建议理清 TCF21与环境毒素和氧化脂质的相互作用及其与环境基因的关系 相互作用导致动脉粥样硬化。在具体目标2中，候选人将在以下方面定义TCF21的功能 利用小鼠动脉粥样硬化模型研究血管平滑肌细胞炎症和病变稳定性。 最终，这项工作将阐明与动脉粥样硬化风险相关的新途径和网络， 引领了新一代治疗学的发展。因此，拟议的工作具有很高的翻译潜力。 本项目的目标是与NHLBI的主要战略目标保持一致，以提高我们对 健康和疾病的分子和生理基础。

PROJECT SUMMARY This five-year K08 proposal will provide the candidate, Juyong Brian Kim, with rigorous training to fulfill specific needs in research and professional development and successfully launch his independent physician-scientist career. The long-term goals are to prepare the candidate for a life-long career as a physician-scientist focused on atherosclerosis and to ultimately improve the management of patients with atherosclerosis through the development of novel therapeutics. The candidate's primary mentor is Dr. Thomas Quertermous, who is an internationally renowned expert in high-throughput genetics, transcriptional regulatory mechanisms, and vascular biology. The candidate is also supported by a committee of advisors and collaborators with expertise in vascular biology and disease, epigenetics and genomics (Drs. William Greenleaf, Gary Owens, Marlene Rabinovitch, Phil Tsao, and Sean Wu). Collectively, the candidate, mentor and advisory committee have formulated a career development plan that will: i) develop the candidate's scientific background for successful research in an important area that parallels his clinical interests; ii) facilitate the candidate's acquisition of new technical skills in cellular and molecular biology and genetics; and iii) provide a mentored transition period between postdoctoral training and independent investigation. The training plan consists of dedicated research time, attendance at meetings to present original work, leadership development, attendance of academic seminars, lectures and journal clubs, formal and informal meetings with the mentor and advisory committee, as well as formal training in the responsible conduct of research. All key personnel have vast experience in the mentorship of trainees. Additionally, Stanford University is committed to providing a maximally supportive environment for the candidate's career development. The candidate will have all resources, infrastructure and support in place to ensure success. The candidate has newly renovated and well equipped laboratory space, the support of clinical colleagues and support staff to ensure at least 80% of his time is protected for research and the support of an abundance of core facilities and shared resources offered through the School of Medicine and through the laboratories of the mentor and advisory committee. Stanford University provides the ideal environment for the candidate's career development. The research topic of this proposal fulfills a significant knowledge gap in the field by identifying a novel mechanism leading to smooth muscle cell inflammation and plaque instability in atherosclerotic lesions. Atherosclerosis is a genetically complex trait that claims more lives than cancer, lung disease and accidents combined. The candidate proposes several hypothesis-driven approaches that will address critical gaps in understanding the genetic basis of atherosclerosis. In Specific Aim 1, the candidate will define the function of TCF21 gene on the inflammatory phenotype of coronary artery smooth muscle cells based on preliminary findings that TCF21 modulates pro-inflammatory networks. He also proposes to untangle the nature of the interaction between TCF21 and environmental toxins and oxidized lipids, as it relates to gene by environment interaction contributing to atherosclerosis. In Specific Aim 2, the candidate will define the function of TCF21 on smooth muscle cell inflammation and lesion stability using mouse models of atherosclerosis. Ultimately, this work will shed light on novel pathways and networks associated with risk for atherosclerosis, leading to development of new class of therapeutics. Thus, the proposed work is of high translational potential. The aims of this project are aligned with the major strategic goal of NHLBI to improve our understanding of the molecular and physiologic basis of health and disease.