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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

基本信息

批准号：
10017667
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
项目类别：
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/10017667
关键词：
Ablation Address Adipocytes Adipose tissue Affect Animal Model Anti-Inflammatory Agents 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 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 professional atmosphere programs research study response skills skin fibrosis transcriptome sequencing transcriptomics translational scientist whole genome

项目摘要

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.

项目摘要这个K 08职业发展奖将提供博士本杰明科曼医学博士。所需的指导培训，确保他发展成为一个独立的研究人员谁将利用实验室为基础的实验方法和组学和生物信息学，以更好地了解系统性硬化症（SSc）的发病机制。候选博士科曼是西北大学医学流变学讲师。他致力于一项事业在学术流变学，并表现出致力于转化研究。他完成了他一年前在西北大学获得风湿病学奖学金，并在他的导师约翰博士那里呆了三年瓦尔加的实验室，他已经产生了令人兴奋的初步数据，支持他目前的建议。在除了稳健的出版记录（15篇出版物，12篇原创高影响力研究文章，包括3篇第一作者原创研究文章，1篇共同第一作者研究文章，3篇第一作者综述在过去的四年里，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。研究计划概述的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， SSc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 SSc中的脂肪分泌因子。为了验证脂肪细胞功能障碍是一个基本过程的假设， SSc发病机制，在目标1，科曼博士将评估如何消融或脂肪扩张的小鼠模型，组织影响硬皮病，脂肪细胞是否是抵抗皮肤纤维化所必需的，以及是否分泌因子介导这种效应。在目标2中，他提出使用脂肪细胞处理的SSc成纤维细胞的离体培养物，衍生因子，以确定脂肪细胞如何发挥其作用的机制，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节，他将利用 RNA-Seq评估全基因组表达，生物信息学解释这些数据。如果成功，这项工作应该导致SSc的生物标志物和治疗方法的发展，目前缺乏这两种疾病。职业发展计划博士科曼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，和密集的导师，将教他独立进行翻译研究，利用小鼠纤维化模型、离体培养系统、RNA-Seq和生物信息学。他的主要导师是博士John Varga是SSc和纤维化的世界专家，拥有超过20年的持续NIH资助，在SSc中的开创性论文，以及出色的指导记录。瓦加博士会确保科曼博士领导专注于SSc的实验室所需的知识和适当的实验室技能。他的共同导师博士。 Davuluri是西北大学生物信息学方面最重要的专家，在信息学以及定期指导，以确保博士科曼成为专家在利用omic 技术和现代计算技术。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。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制研究，2）学习如何利用，计算分析，解释高通量omic数据的结果，3）磨练他的领导力，组织，沟通，授予写作技能和4）发表研究结果，并获得独立的R 01级资金。制度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。西北大学为科曼博士提供了来自流变学系的专门支持，医学系; 2）导师和合作者的多学科团队; 3）课程，研讨会，与其职业发展相关的科学会议; 4）包括实验室空间在内的研究基础设施，设备，多个相关的核心设施和生物信息学支持; 5）各种各样的职业发展工作坊;以及6）每周至少有75%的时间受到保护，每周有半天的以SSC为重点的风湿病诊所每年只有一到两周的风湿病住院咨询工作。总结博士科曼的职业目标是成为一个独立的翻译研究人员谁利用国家的最先进的实验室和计算技术，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，提交研究结果供发表，并继续发展基于实验室的细胞和分子生物学的专业知识，以及高通量使用生物信息学的实验室数据平台。从长远来看，这项工作将成为R 01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，在此奖项期间获得开发精确医学策略，可以有效地治疗SSc患者。