This proposal describes a five-year research and training plan that will facilitate the transition of Dr. Robert Guzy, MD, PhD to an independent academic researcher. Dr. Guzy is a cell and molecular biologist and adult pulmonologist at the University of Chicago, and is building a career as a physician scientist with an interest in lung injury and pulmonary fibrosis. He has a strong background in basic science research and medicine and has completed post-graduate training in Internal Medicine and Pulmonary/Critical Care Medicine. The primary training goal of this K08 proposal is to provide the framework and support necessary for Dr. Guzy to 1) extend his experience with murine models of lung injury, 2) build a fund of knowledge in macrophage biology, 3) develop expertise in translational studies, 4) develop expertise in transcriptomics, and 5) transition to independent scientific investigation in pulmonary disease. This work will be carried out at The University of Chicago under the supervision of Dr. Gokhan Mutlu, MD. The University of Chicago is renowned for its strength in many research disciplines, including translational pulmonary medicine. Dr. Mutlu is an international leader in lung injury research and macrophage biology, and has a highly successful track record of mentoring. An advisory committee with diverse expertise will provide career guidance and scientific feedback. A detailed career development plan is proposed that includes a timeline for development of new skills, preparation of manuscripts for publication, and an eventual R01 application in a pathway to independence. The proposed research plan will focus on mechanistic studies of FGF2 signaling in lung injury. Preliminary studies performed by Dr. Guzy demonstrate that FGF2 is expressed in macrophages in response to lung injury in mice and humans. Furthermore, mice lacking FGF2 (Fgf2-/-) have increased mortality and deficient alveolar epithelial recovery in response to bleomycin. This study proposes a model in which macrophage-derived FGF2 is required for recovery from lung injury by directly promoting proliferation of lung epithelium and subsequent differentiation into mature alveolar epithelial cells. This will be approached with three Specific Aims:
Aim 1 : Determine the requirement of macrophage-derived FGF2 expression in response to lung injury.
Aim 2 : Determine the requirement of FGFRs in Type 2 AECs for recovery after lung injury.
Aim 3 : Determine the capacity for FGF2 to provide an enhanced reparative signal after lung injury. In total, these studies will be critical for developing a mechanism of FGF2/FGFR-mediated epithelial recovery after lung injury, and will be the basis for future applications of FGF2 to promote recovery in patients with ARDS. Additionally, results of this project will serve as a foundation for future NIH R01 applications and a career as an independent pulmonary physician scientist.

Public Health Relevance

Acute Lung Injury and Acute Respiratory Distress Syndrome (ARDS) affect approximately 200,000 people per year, resulting in 3.6 million hospital days and 75,000 deaths per year1, and despite continued improvements in supportive care outcomes in ARDS are poor, with up to a 30% mortality rate2. Injury to the epithelial lining of the lung is a key component to the pathogenesis of lung injury and ARDS, and understanding processes that promote recovery from lung epithelial injury is crucial for development of novel therapeutics. The proposed studies aim to clarify mechanisms of fibroblast growth factor-mediated epithelial repair after lung injury and determine the potential for fibroblast growth factors as novel therapeutics in lung injury and ARDS.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Clinical Investigator Award (CIA) (K08)
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Special Emphasis Panel (MCBS (JA))
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Reineck, Lora A
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University of Chicago
Internal Medicine/Medicine
Schools of Medicine
United States
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