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.

Public Health Relevance

Emphysema is a major component of chronic obstructive pulmonary disease (COPD), which is the 3rd leading cause of mortality worldwide and is increasing in incidence and cost, despite significant research effort. Follistatin-like protein 1 (FSTL-1) appears to inhibit emphysema development by an unknown mechanism, and the role of FSTL-1 in lung inflammation has not been explored. This proposal aims to examine the role of FSTL-1 in the lung and the underlying mechanisms by which it exerts a protective effect against emphysema development.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08HL128809-03
Application #
9278270
Study Section
Special Emphasis Panel (MCBS (MA))
Program Officer
Tigno, Xenia
Project Start
2015-09-01
Project End
2020-05-31
Budget Start
2017-06-01
Budget End
2018-05-31
Support Year
3
Fiscal Year
2017
Total Cost
$135,378
Indirect Cost
$10,028
Name
University of Pittsburgh
Department
Pediatrics
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Evangelista, Eric A; Lemaitre, Rozenn N; Sotoodehnia, Nona et al. (2018) CYP2J2 Expression in Adult Ventricular Myocytes Protects Against Reactive Oxygen Species Toxicity. Drug Metab Dispos 46:380-386
Eddens, Taylor; Kaplan, Daniel J; Anderson, Alyce J M et al. (2018) Insights from the Geographic Spread of the Lyme Disease Epidemic. Clin Infect Dis :
Zeigler, Maxwell; Whittington, Dale; Sotoodehnia, Nona et al. (2018) A sensitive and improved throughput UPLC-MS/MS quantitation method of total cytochrome P450 mediated arachidonic acid metabolites that can separate regio-isomers and cis/trans-EETs from human plasma. Chem Phys Lipids 216:162-170
Eddens, Taylor; Elsegeiny, Waleed; Garcia-Hernadez, Maria de la Luz et al. (2017) Pneumocystis-Driven Inducible Bronchus-Associated Lymphoid Tissue Formation Requires Th2 and Th17 Immunity. Cell Rep 18:3078-3090
Campfield, Brian T; Eddens, Taylor; Henkel, Matthew et al. (2017) Follistatin-like protein 1 modulates IL-17 signaling via IL-17RC regulation in stromal cells. Immunol Cell Biol 95:656-665
Eddens, Taylor; Campfield, Brian T; Serody, Katelin et al. (2016) A Novel CD4+ T Cell-Dependent Murine Model of Pneumocystis-driven Asthma-like Pathology. Am J Respir Crit Care Med 194:807-820
Chen, Kong; Campfield, Brian T; Wenzel, Sally E et al. (2016) Antiinflammatory effects of bromodomain and extraterminal domain inhibition in cystic fibrosis lung inflammation. JCI Insight 1: