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.

项目摘要 该K08职业发展奖将为本杰明·科尔曼（Benjamin Korman）博士提供所需的修订培训 确保他发展成为独立的研究人员，他将利用这两个基于实验室的实验 方法和毛刺和生物信息学以更好地了解系统性硬化症的发病机理（SSC）。 候选人 Korman博士是西北大学的医学 - 鲁姆病学讲师。他致力于职业 在学术风湿病学中，已经表现出对翻译研究的承诺。他完成了 一年前在西北地区的风湿病学研究金，他的导师约翰博士度过了三年 瓦尔加（Varga）的实验室（Varga's Laboratory）产生了令人兴奋的初步数据，以支持他当前的提议。在 除了强大的出版物记录（15个出版物，12篇原始高影响力研究文章，包括3个 首先撰写的原始研究文章，一篇联合首选的研究文章和3篇第三本书的评论 文章），在过去的四年中，他还成功地获得了资金，包括T32培训补助金， Niams个人F32奖和机构BIRCWH K12奖，目前支持他的工作。 研究计划 该研究计划概述了脂肪细胞调节皮肤纤维化的最新证据，在 SSC发病机理，正常脂肪纤维细胞稳态的破坏会导致不健康的水平 SSC中的脂肪分泌因子。测试脂肪细胞功能障碍是一个基本过程的假设 SSC发病机理，在AIM 1中，Korman博士将评估脂肪消融或扩展的小鼠模型 组织撞击硬皮病，脂肪细胞是否需要抵抗皮肤纤维化，以及分泌的因素 调解这种效果。在AIM 2中，他提出使用脂肪细胞治疗的SSC成纤维细胞的体内培养物 得出的因素来确定脂肪细胞如何执行其效果以及哪个分泌的机制 因素可能与SSC有关。为了更好地了解这些过程的细胞调节，他将利用 RNA-Seq评估整个基因组表达和生物信息学以解释这些数据。如果成功，这项工作 应该导致生物标志物的发展和SSC治疗，这是目前缺乏两者的疾病。 职业发展计划 Korman博士将通过一项由正式的职业发展计划实现自己的职业目标 课程工作和密集的心态将教会他独立进行翻译研究 利用纤维化，离体培养系统，RNA-Seq和生物信息学的小鼠模型。他的主要心理是 约翰·瓦尔加（John Varga）博士是SSC和纤维化的世界专家，拥有20多年的连续NIH资金，数百份 SSC中的第二篇论文，以及出色的指导记录。 Varga博士将确保Korman博士获得 领导着专注于SSC的实验室所需的知识和适当的实验室技能。他的同事博士 Davuluri是西北地区生物信息学的最重要专家，将提供正式的教学培训 在信息信息和定期心理方面，以确保Korman博士成为使用OMIC的专家 技术和现代计算技术。科尔曼博士的职业发展将基于工作 达到四个明确且可实现的目标。其中包括1）发展设计和执行技能 使用体内和体内系统的机械研究，2）学习如何利用，计算分析和 解释高通量imic数据的结果，3）蜂蜜的领导，组织，沟通和 授予写作技巧和4）发表研究结果并获得独立的R01级资金。 机构环境 这项工作将在西北大学完成，这是一个理想的培训环境。 西北向科曼博士提供1）风湿病学和 医学系； 2）由导师和合作者组成的多学科团队； 3）课程，半手和 与他的职业发展有关的科学会议； 4）包括实验室空间和包括实验室空间的研究基础设施 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 讲习班； 6）至少有75％的时间为以SSC为中心的风湿病学诊所每周的半天保护时间 每年只有一周的住院风湿病学咨询税。 概括 科尔曼博士的职业目标是成为一名独立翻译的研究人员，他利用最先进的 实验室和计算技术，以更好地了解SSC的发病机理。在短期内，他 将填写提案中概述的实验，提交研究结果以供出版，然后继续 在基于实验室的细胞和分子生物学以及高通量的整合方面发展专业知识 使用生物信息学的实验室数据的平台。从长远来看，这项工作将构成R01的基础 并推动Korman博士成为SSC系统生物学的领导者，他们将利用他的技能 在此奖励期间获得的，以制定可以有效治疗SSC患者的精密中等医学策略。