Contribution of Adipocytes and Adipose Secreted Factors to Fibrosis in Systemic Sclerosis

项目摘要 K08职业发展奖将为本杰明·科曼医学博士提供必要的指导培训，以 确保他发展成为一名独立的研究员，他将利用基于实验室的实验 更好地了解系统性硬化症(SSC)的发病机制的方法和组学和生物信息学。 侯选人 科曼博士是西北大学的风湿病医学讲师。他献身于自己的事业。 在学术风湿学方面，并表现出对翻译研究的承诺。他完成了他的 一年前在西北大学获得风湿病研究员资格，并在他的导师约翰博士那里度过了三年 瓦尔加的实验室，他在那里产生了令人兴奋的初步数据，支持他目前的提议。在……里面 除了强劲的出版记录(15篇出版物，12篇原创的高影响力研究文章，包括3篇 第一篇原创研究文章，一篇联合第一篇研究文章，3篇第一作者评论 文章)，在过去的四年中，他还成功地获得了包括T32培训补助金在内的资金， 个人NIAMS F32奖和机构BIRCWH K12奖，目前支持他的工作。 研究计划 这项研究计划建立在最近的证据基础上，即脂肪细胞调节皮肤纤维化，在 SSC的发病机制，以及正常脂肪-成纤维细胞稳态的破坏导致不健康的水平 SSC中的脂肪分泌因子。为了验证脂肪细胞功能障碍是 SSC的发病机制，在目标1中，Korman博士将评估小鼠模型如何消融或扩大脂肪 组织冲击性硬皮病，脂肪细胞是否是抵抗皮肤纤维化所必需的，以及是否有分泌因子 调停这一效应。在目标2中，他建议使用脂肪细胞处理的SSC成纤维细胞的体外培养 决定脂肪细胞如何发挥其作用和分泌哪些物质的机制的衍生因子 这些因素可能与SSC有关。为了更好地理解这些过程的细胞调控，他将利用 RNA-Seq用于评估全基因组表达，生物信息学用于解释这些数据。如果成功，这项工作 应该导致针对SSc的生物标记物和治疗学的开发，SSC是一种目前缺乏这两种疾病的疾病。 职业发展计划 科曼博士将通过职业发展计划实现他的职业目标，该计划包括正式的 课程作业和密集的指导，这将教会他独立进行翻译研究 利用小鼠纤维化模型、体外培养系统、RNA-Seq和生物信息学。他的主要导师是 约翰·瓦尔加博士是干细胞和纤维化方面的世界专家，拥有超过20年的NIH连续资助，数百名 SSC的开创性论文，以及出色的指导记录。瓦尔加博士将确保科曼博士获得 领导一个专注于SSC的实验室所需的知识和适当的实验室技能。他的合作导师Dr。 Davuluri是西北大学生物信息学方面的顶尖专家，他将提供两种正式的教学培训 在信息学和常规指导方面，以确保Korman博士成为利用OMIC的专家 技术和现代计算技术。科曼博士的职业发展将以工作为基础 朝着四个明确和可实现的目标前进。这些包括1)发展设计和执行的技能 使用体内和体外系统的机械研究，2)学习如何利用，计算分析，和 解读高通量数据的结果，3)磨练其领导力、组织、沟通和 授予写作技能；4)发表研究研究成果并获得独立的R01级资助。 制度环境 这项工作将在西北大学完成，这是一个理想的训练环境。 西北大学为科曼博士提供1)风湿科和风湿科的专门支持 医学系；2)由导师和合作者组成的多学科团队；3)课程、研讨会和 与其职业发展相关的科学会议；4)研究基础设施，包括实验室空间和 设备、多个相关核心设施和生物信息学支持；5)各种各样的职业发展 研讨会；以及6)至少75%的保护时间，每周半天以SSC为重点的风湿病诊所 而且每年只有一到两周的风湿病住院患者会诊值班。 摘要 科曼博士的职业目标是成为一名独立的翻译研究员，利用最先进的技术 实验室和计算技术，以更好地了解SSc的发病机制。在短期内，他 将完成提案中概述的实验，提交研究结果以供发表，并继续 发展以实验室为基础的细胞和分子生物学的专业知识，并整合高通量 利用生物信息学提供实验室数据的平台。从长远来看，这项工作将构成R01的基础 并推动科曼博士成为SSC系统生物学的领导者，他将利用他的技能 在该奖项期间获得，以开发能够有效治疗SSc患者的精准医学策略。

Project Summary This K08 career development award will provide Dr. Benjamin Korman M.D. the needed mentored training to ensure that he develops into an independent researcher who will utilize both laboratory-based experimental approaches and omics and bioinformatics to better understand the pathogenesis of systemic sclerosis (SSc). Candidate Dr. Korman is an Instructor in Medicine-Rheumatology at Northwestern University. He is dedicated to a career in academic rheumatology and has shown commitment to translational research. He completed his rheumatology fellowship at Northwestern one year ago, and has spent three years in his mentor Dr. John Varga’s laboratory where he has generated exciting preliminary data which support his current proposal. In addition to a robust publication record (15 publications, 12 original high-impact research articles including 3 first-authored original research articles, one co-first authored research article, and 3 first-authored review articles), in the last four years, he has also been successful in obtaining funding including a T32 training grant, an individual NIAMS F32 award, and an institutional BIRCWH K12 award which currently supports his work. Research Plan The research plan outlined builds on recent evidence that adipocytes modulate skin fibrosis, play a key role in SSc pathogenesis, and that a disruption in normal adipose-fibroblast homeostasis leads to unhealthy levels of adipose secreted factors in SSc. To test the hypothesis that adipocyte dysfunction is a fundamental process in SSc pathogenesis, in Aim 1, Dr. Korman will assess how mouse models of ablation or expansion of adipose tissue impact scleroderma, whether adipocytes are necessary to resist skin fibrosis, and if secreted factors mediate this effect. In Aim 2, he proposes to use ex vivo cultures of SSc fibroblasts treated with adipocyte derived factors to determine the mechanism as to how adipocytes exert their effects and which secreted factors may be relevant to SSc. To better understand the cellular regulation of these processes, he will utilize RNA-Seq to assess whole genome expression and bioinformatics to interpret this data. If successful, this work should lead to the development of biomarkers and therapeutics for SSc, a disease which currently lacks both. Career Development Plan Dr. Korman will achieve his career goals through a career development plan that consists of formal coursework, and intensive mentorship that will teach him to independently perform translational research which utilizes mouse models of fibrosis, ex vivo culture systems, RNA-Seq, and bioinformatics. His primary mentor is Dr. John Varga, a world expert in SSc and fibrosis with over 20 years of continuous NIH funding, hundreds of seminal papers in SSc, and an outstanding record of mentoring. Dr. Varga will ensure that Dr. Korman obtains the knowledge and appropriate laboratory skills necessary to head a lab focused on SSc. His co-mentor Dr. Davuluri is the foremost expert in bioinformatics at Northwestern and will provide both formal didactic training in informatics as well as regular mentoring to ensure that Dr. Korman becomes an expert in utilizing omic technologies and modern computational techniques. Dr. Korman’s career development will be based on work toward four well-defined and attainable goals. These include 1) to develop the skills to design and execute mechanistic research using in vivo and ex vivo systems, 2) to learn how to utilize, computationally analyze, and interpret the results of high-throughput omic data, 3) hone his leadership, organizational, communication, and grant writing skills and 4) to publish research study results and obtain independent R01-level funding. Institutional Environment The work will be accomplished at Northwestern University which is an ideal training environment. Northwestern provides Dr. Korman with 1) dedicated support from the Division of Rheumatology and Department of Medicine; 2) a multidisciplinary team of mentors and collaborators; 3) courses, seminars, and scientific meetings relevant to his career development; 4) a research infrastructure that includes lab space and equipment, multiple relevant core facilities, and bioinformatics support; 5) a wide variety of career development workshops; and 6) at least 75% protected time with one half-day of SSc-focused rheumatology clinic weekly and only one-two weeks of inpatient rheumatology consult duty per year. Summary Dr. Korman’s career goal is to become an independent translational researcher who utilizes state-of-the-art laboratory and computational techniques to better understand the pathogenesis of SSc. In the short-term, he will complete the experiments outlined in the proposal, submit study results for publication, and continue to develop expertise in laboratory-based cellular and molecular biology, and integration of high-throughput platforms with laboratory data using bioinformatics. In the long-term, this work will form the basis for an R01 and propel Dr. Korman to become a leader in the systems biology of SSc who will leverage the skills he obtains during this award to develop precision-medicine strategies that can effectively treat patients with SSc.