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：
9495584
负责人：
BRIAN T CAMPFIELD
金额：
$ 13.86万
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/9495584
关键词：
Accounting Adult Air Albumins Alveolar Animals Autoimmune Process Birth Bulla CC chemokine receptor 2 CCL2 gene Cartilage Cells Childhood Chronic Obstructive Airway Disease 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 Immune Immunity Immunohistochemistry Immunologics In Situ Hybridization Incidence Individual Inflammation Inflammatory Interleukin-1 beta Interleukin-17 Interleukin-6 Introns Investigation Journals K-Series Research Career Programs Knock-out Knockout Mice Ligands Literature Lobular Lung Lung Inflammation MME gene MMP9 gene Matrix Metalloproteinases Measures Mediating Mediator of activation protein Mentors Mentorship Mesenchymal Microscopic Modality Modeling Molecular Target Mus Nature Pathology Pathway interactions Pediatric Hospitals Pediatrics Peptide Hydrolases Perinatal mortality demographics Phenotype Physicians Play Pleural Pre-Clinical Model Production Proteins Pulmonary Emphysema Research Research Personnel Role Scholarship Scientist Signal Transduction Site Skeletal Development Smoke 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 experimental study improved in vivo inflammatory lung disease innovation interleukin-23 lung development macrophage medical schools mortality mouse model novel postnatal prevent professor programs promoter protective effect public health relevance receptor recruit research and development 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（由申请人提供）：本指导临床科学家研究职业发展奖提案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。坎普菲尔德在匹兹堡大学医学院获得医学博士学位，并在匹兹堡儿童医院完成了儿科和儿科传染病培训。卵泡抑素样蛋白 1 (FSTL-1) 通过抑制导致肺气肿的炎症和蛋白酶活性，在肺稳态中发挥关键作用。肺气肿是 COPD 的常见组成部分，而 COPD 是世界上第三大死亡原因。美国预计花费 500 亿美元 COPD 的死亡率、发病率和费用持续增加，因此迫切需要改进我们目前对慢性阻塞性肺病的预防、诊断和治疗方式。病理生理学不完整，许多当前的临床前模型重现人类肺气肿复杂病理生理学的能力有限。Campfield 博士的研究项目观察到，全局、条件性 FSTL-1 基因敲除小鼠会自发出现肺气肿，并且这种表型与 Type 增加特别相关。 17 细胞因子、肺部基质金属蛋白酶表达增加和蛋白酶活性过高此外，利用计算机断层扫描，他们能够识别肺气肿变化。 Campfield 博士提出，FSTL-1 对于正常的肺稳态至关重要，因此 FSTL-1 的缺失会导致肺气肿，具体而言，FSTL-1 会直接限制产生 IL-17 的细胞的募集。 CCR2 和 IL17R 配体在肺中的表达，并且 FSTL-1 减少了表达 MMP12 的巨噬细胞的募集，而巨噬细胞有助于肺气肿的发展。三个目标：1) 确定 FSTL-1 在肺部的时空表达以及 fstl1 条件性敲除 (CKO) 在不同出生后时间点的影响，2) 确定肺中 IL-17 受体和 C-C 趋化因子受体 2 信号传导的需求使用 FSTL-1 CKO 确定肺气肿的发展，3) 确定肺固有 fstl1 表达与循环 FSTL-1 在预防肺气肿发展中的作用。坎普菲尔德博士的职业发展计划建立在几个支柱之上：严格的实验研究；负责任的机构学术发展和资助的高质量文献、资助和期刊审查；他的研究指导主要来自 NIH 资助的杰出肺病学家 Jay Kolls 博士，他的开创性研究帮助确定了 IL-17 在肺部免疫和炎症中的作用。Campfield 博士也将得到指导。奖学金指导委员会由三名成功的医师科学家组成，他执行了这项提案并过渡到独立调查员的职业生涯。