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

 描述（由申请人提供）：这份指导临床科学家研究职业发展奖的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。Campfield博士获得了医学博士学位。他毕业于匹兹堡大学医学院，并在匹兹堡儿童医院完成了儿科和儿科传染病培训。该提议建立在新的观察基础上，即卵泡抑素样蛋白1（FSTL-1）通过抑制导致肺气肿的炎症和蛋白酶活性在肺内稳态中起关键作用。肺气肿是COPD的常见组成部分，COPD是世界上第三大死亡原因，在美国估计成本为500亿美元。COPD的死亡率、发病率和成本持续增加，认为迫切需要改进的预防、诊断和治疗方式。我们目前对病理生理学的理解是不完整的，并且许多当前的临床前模型再现人类肺气肿的复杂病理生理学的能力有限。Campfield博士的研究项目已经观察到，一个全球性的、条件性的FSTL-1敲除小鼠自发地发展为肺气肿，并且这种表型与肺中17型细胞因子增加、基质金属蛋白酶表达增加和蛋白酶活性过度特别相关。此外，使用计算机断层扫描，他们能够识别肺气肿变化，这将允许研究个体动物纵向。 Campfield博士假设FSTL-1对正常肺内稳态至关重要，因此FSTL-1的缺失导致肺气肿。具体地，FSTL-1直接限制了驱动肺中CCR 2和IL 17 R配体表达的IL-17产生细胞的募集，并且FSTL-1减少了促进肺气肿发展的表达MMP 12的巨噬细胞的募集。将沿着沿着三个目标检验这一假设：1）测定肺中FSTL-1的时空表达和出生后不同时间点fstl 1条件性敲除（CKO）的作用，2）使用FSTL-1 CKO测定肺气肿发展中IL-17受体和C-C趋化因子受体2信号传导的需要，和3）确定肺内在FSTL 1表达相对于循环FSTL-1在预防肺气肿发展中的作用。 Campfield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;正式的学术课程;高质量的文献，赠款和期刊评论;在负责任的研究行为中进行面对面的培训;机构学术发展和赠款写作研讨会。他的研究导师将主要来自Jay Kolls博士，他是一位杰出的NIH资助的肺病学家，其开创性研究帮助定义了IL-17在肺部免疫和炎症中的作用。Campfield博士还将接受由三名成功的医生-科学家组成的奖学金指导委员会的指导，因为他执行这一建议并过渡到作为独立研究者的职业生涯。

 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.