A Critical Role for Follistatin-like Protein-1 in Lung Homeostasis

卵泡抑素样蛋白 1 在肺稳态中的关键作用

基本信息

批准号：
8947692
负责人：
BRIAN T CAMPFIELD
金额：
$ 12.68万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-01 至 2020-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8947692
关键词：
Accounting Adult Air Albumins Alveolar Animals Autoimmune Process Birth Bulla CC chemokine receptor 2 Cartilage Cells Childhood Chronic Obstructive Airway Disease Cigarette smoke-induced emphysema Clinical Collagen-Induced Arthritis Communicable Diseases Complex Cytokine Signaling Data Defect Development Development Plans Diagnostic Disease Doctor of Medicine Educational workshop Epithelial Cells Exons Follistatin-Related Protein 1 Functional disorder Funding Gelatinase B Genitourinary system Goals Grant Histology Homeostasis Human Immunity Immunohistochemistry In Situ Hybridization Incidence Individual Inflammation Inflammatory Interleukin-17 Interleukin-6 Introns Investigation Journals K-Series Research Career Programs Knock-out Knockout Mice Ligands Literature Lobular Lung Lung Inflammation MMP9 gene Matrix Metalloproteinases Measures Mediating Mediator of activation protein Medicine Mentors Mentorship Mesenchymal Microscopic Modality Modeling Molecular Target Monocyte Chemoattractant Protein-1 Mus Nature Pathology Pathway interactions Pediatric Hospitals Pediatrics Peptide Hydrolases Perinatal Phenotype Physicians Play Pleural Pre-Clinical Model Production Proteins Pulmonary Emphysema Research Research Personnel Role Scholarship Schools Scientist Signal Transduction Site Skeletal Development Structure Tamoxifen Techniques Testing Therapeutic Time Tissue Model Tissues Training Transgenic Mice United States National Institutes of Health Universities Work Writing X-Ray Computed Tomography base beta-Chemokines career career development chemokine receptor cost cytokine immune function improved in vivo inflammatory lung disease innovation interleukin-23 lung development macrophage mortality mouse model novel postnatal prevent professor programs promoter protective effect public health relevance receptor research and development research study responsible research conduct

项目摘要

DESCRIPTION (provided by applicant): This proposal for a Mentored Clinical Scientist Research Career Development Award describes the career goals, career development plan and research strategy for Dr. Brian Campfield, Assistant Professor of Pediatrics at the University Of Pittsburgh School Of Medicine. Dr. Campfield obtained his M.D. from the University Of Pittsburgh School Of Medicine, and completed his Pediatric and Pediatric Infectious Diseases training at the Children's Hospital of Pittsburgh. This proposal builds upon the novel observation that Follistatin- like protein 1 (FSTL-1) plays a critical role in lung homeostasis by inhibiting inflammation and protease activity that results in emphysema. Emphysema is a common component of COPD, which is the 3rd leading cause of mortality in the world accounting for an estimated cost of $50 billion in the U.S. The mortality, incidence and cost of COPD continue to increase arguing that improved preventative, diagnostic and therapeutic modalities are urgently needed. Our current understanding of the pathophysiology is incomplete and many current preclinical models have limited ability to reproduce the complex pathophysiology of human emphysema. Dr. Campfield's research program has observed that a global, conditional FSTL-1 knockout mouse spontaneously develops emphysema, and this phenotype is associated specifically with increased Type 17 cytokines, increased matrix metalloproteinase expression and excessive protease activity in the lung. Additionally, using computed tomography they are able to identify emphysematous changes that will allow for the study individual animals longitudinally. Dr. Campfield hypothesizes that FSTL-1 is critical for normal lung homeostasis such that loss of FSTL-1 results in emphysema. Specifically, FSTL-1 directly limits the recruitment of IL-17 producing cells that drive expression of CCR2 and IL17R ligands in the lung, and FSTL-1 lessens the recruitment of MMP12 expressing macrophages that contribute to the development of emphysema. This hypothesis will be tested along three aims: 1) determine the temporospatial expression of FSTL-1 in the lung and effect of fstl1 conditional knock-out (CKO) at various postnatal time points, 2) determine the requirement of IL-17 receptor and C-C chemokine receptor 2 signaling in emphysema development using the FSTL-1 CKO, and 3) determine role of the lung intrinsic fstl1 expression versus circulating FSTL-1 in preventing the development of emphysema. Dr. Campfield has a Career Development Plan built upon several pillars: rigorous experimental studies; formal academic coursework; high-quality literature, grant and journal review; face-to-face training in the responsible conduct of research; institutional academic development and grant-writing workshops. His research mentorship will primarily come from Dr. Jay Kolls, an outstanding NIH-funded pulmonologist whose pioneering studies have helped define the role of IL-17 in immunity and inflammation in the lung. Dr. Campfield will also receive guidance by a Scholarship Mentoring Committee comprised of three successful physician- scientists as he executes this proposal and transitions to a career as an independent investigator.

描述（由适用提供）：该指导的临床科学家研究职业发展奖的这一建议描述了匹兹堡大学医学院儿科助理教授Brian Campfield博士的职业目标，职业发展计划和研究策略。坎普菲尔德博士从匹兹堡大学医学院获得了医学博士学位，并在匹兹堡儿童医院完成了他的儿科和儿科传染病培训。该提议建立在新的观察结果上，即Follistatin-like蛋白1（FSTL-1）通过抑制导致肺气肿的注射和蛋白酶活性，在肺稳态中起关键作用。肺气肿是COPD的共同组成部分，COPD是世界上死亡率的第三主要原因，估计在美国的估计成本为500亿美元，COPD的死亡率，发病率和成本继续增加，认为改善预防，诊断和治疗方式的改善是必需的。我们目前对病理生理学的理解是不完整的，许多当前的临床前模型具有有限的重现人肺气肿的复杂病理生理能力。坎普菲尔德博士的研究计划已经观察到，全球条件的FSTL-1基因敲除小鼠赞助发展肺气肿，并且该表型特别与增加的17型细胞因子，增加的基质金属蛋白酶表达和肺中过量的蛋白酶活性有关。此外，使用计算机断层扫描，他们能够识别出延长研究的单个动物的杂质变化。 Campfield博士假设FSTL-1对于正常的肺稳态至关重要，因此FSTL-1的丧失会导致肺气肿。特别是，FSTL-1直接限制了IL-17产生的细胞的募集，这些细胞驱动肺中CCR2和IL17R配体的表达，而FSTL-1减少了表达巨噬细胞的MMP12的募集，这些巨噬细胞有助于造成杂技发育。该假设将沿三个目的进行检验：1）确定FSTL-1在肺中的临时孔道表达和FSTL1条件敲除（CKO）在各种产后时间点的效果，2）确定IL-17受体和C-C-C-C-C介质受体2在使用FSTL-1 CKO的表达中的表达中的C-C-C介质受体2信号的需求。 FSTL-1防止肺气肿的发展。坎普菲尔德博士的职业发展计划建立在几个支柱上：严格的实验研究；正式的学术课程；高质量文献，赠款和期刊评论；负责任进行研究的面对面培训；机构学院发展和赠款写作研讨会。他的研究心态将来自一位出色的NIH资助的脉搏器学家杰伊·科尔斯（Jay Kolls）博士，其开创性研究有助于确定IL-17在肺中免疫和炎症中的作用。坎普菲尔德博士还将获得奖学金指导委员会的指导，该委员会完成了三名成功的物理科学家，因为他执行了这一建议并过渡到职业生涯。