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

脂肪细胞和脂肪分泌因子对系统性硬化症纤维化的贡献

• 批准号: 9636931
• 负责人: Benjamin Douglas Korman
• 金额: $ 15.72万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-01 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9636931
• 关键词: Ablation; Address; Adipocytes; Adipose tissue; Affect; Animal Model; Anti-inflammatory; Award; Bioinformatics; Biological Markers; Biology; Bleomycin; Case Fatality Rates; Cells; Clinic; Clinical Oncology Supplement (K12); Collagen; Communication; Complex; Computational Technique; Connective Tissue Diseases; Consult; Core Facility; Data; Dermal; Development Plans; Disease; Doctor of Medicine; Educational workshop; Effector Cell; Ensure; Environment; Equipment; Event; Fellowship; Fibroblasts; Fibrosis; Functional disorder; Funding; Future; Genetic; Genomics; Goals; Grant; Head; Homeostasis; Individual; Informatics; Inpatients; K-Series Research Career Programs; Knowledge; Laboratories; Lead; Leadership; Learning; Left; Mediating; Medicine; Mentors; Mentorship; Metabolic; Methods; Modernization; Molecular; Molecular and Cellular Biology; Morbidity - disease rate; Mus; Myofibroblast; National Institute of Arthritis and Musculoskeletal and Skin Diseases; Organ; Paper; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Phenotype; Play; Process; Proliferating; Property; Proteins; Publications; Publishing; Regulation; Research; Research Infrastructure; Research Personnel; Rheumatology; Role; Scleroderma; Seminal; Signal Transduction; Skin; Skin injury; Stress; System; Systemic Scleroderma; Systems Biology; Technology; Testing; Therapeutic; Time; Training; Translational Research; United States National Institutes of Health; Universities; Work; Writing; adipokines; base; biomarker development; career; career development; cell growth regulation; collaborative environment; cytokine; design; effective therapy; experimental study; fibrogenesis; in vivo; indium-bleomycin; insight; instructor; meetings; mortality; mouse model; multidisciplinary; next generation sequencing; novel; paracrine; precision medicine; programs; research study; response; skills; skin fibrosis; transcriptome sequencing; transcriptomics; translational scientist; whole genome

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.

项目概要 该 K08 职业发展奖将为 Benjamin Korman 医学博士提供所需的指导培训 确保他发展成为一名独立的研究人员，能够利用基于实验室的实验 方法以及组学和生物信息学，以更好地了解系统性硬化症（SSc）的发病机制。 候选人 科曼博士是西北大学医学风湿病学讲师，他致力于自己的职业生涯。 他拥有学术风湿病学博士学位，并致力于转化研究。 一年前在西北大学获得风湿病学奖学金，并在导师约翰博士的指导下度过了三年 瓦尔加的实验室生成了令人兴奋的初步数据，支持他当前的提议。 除了稳健的发表记录（15 篇出版物、12 篇原创高影响力研究文章，其中 3 篇） 第一作者原创研究文章、一篇共同第一作者研究文章和 3 篇第一作者评论 文章），在过去的四年里，他还成功获得了资金，包括 T32 培训补助金， 个人 NIAMS F32 奖和机构 BIRCWH K12 奖目前支持他的工作。 研究计划 该研究计划概述的基础是最近的证据，即脂肪细胞调节皮肤纤维化，在 SSc 发病机制，正常脂肪成纤维细胞稳态的破坏会导致不健康的脂肪成纤维细胞水平 SSc 中的脂肪分泌因子 检验脂肪细胞功能障碍是 SSc 中一个基本过程的假设。 SSc 发病机制，在目标 1 中，Korman 博士将评估小鼠模型的脂肪消融或扩张如何 组织对硬皮病的影响，脂肪细胞是否是抵抗皮肤纤维化所必需的，以及是否分泌因子 在目标 2 中，他建议使用经脂肪细胞处理的 SSc 成纤维细胞的离体培养物。 衍生因素来确定脂肪细胞如何发挥其作用以及分泌哪些机制 为了更好地了解这些过程的细胞调节，他将利用可能与 SSc 相关的因素。 RNA-Seq 评估全基因组表达，并通过生物信息学解释该数据。如果成功，这项工作就可以完成。 应该会导致 SSc 生物标志物和治疗方法的开发，而目前这两种疾病都缺乏。 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将教会他独立进行转化研究 他利用小鼠纤维化模型、离体培养系统、RNA-Seq 和生物信息学。 John Varga 博士是 SSc 和纤维化方面的世界专家，拥有 20 多年持续 NIH 资助、数百名 SSc 中的开创性论文以及 Varga 博士出色的指导记录将确保 Korman 博士获得成功。 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。 Davuluri 是西北大学生物信息学领域最重要的专家，将提供正式的教学培训 信息学以及定期指导，以确保 Korman 博士成为利用 omic 的专家 科曼博士的职业发展将基于工作。 实现四个明确且可实现的目标，其中包括 1) 培养设计和执行技能。 使用体内和离体系统进行机械研究，2) 学习如何利用、计算分析和 解释高通量组学数据的结果，3）磨练他的领导力、组织能力、沟通能力和 授予写作技能，4）发表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，西北大学是一个理想的培训环境。 西北大学为 Korman 博士提供 1) 风湿病科的专门支持，以及 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 与他的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）广泛的职业发展； 研讨会；以及 6) 每周至少 75% 的受保护时间有半天的 SSc 风湿病门诊 每年只有一到两周的住院风湿病咨询值班。 概括 Korman 博士的职业目标是成为一名利用最先进技术的独立转化研究员 短期内，他利用实验室和计算技术更好地了解 SSc 的发病机制。 将完成提案中概述的实验，提交研究结果以供发表，并继续 发展基于实验室的细胞和分子生物学以及高通量整合的专业知识 从长远来看，这项工作将构成 R01 的基础。 并推动 Korman 博士成为 SSc 系统生物学领域的领导者，他将利用他所掌握的技能 在此奖项中获得开发能够有效治疗 SSc 患者的精准医疗策略。