The global objective of this NRSA Individual Fellowship Application is to facilitate development of essential skills that will allow the candidae to become an academic physician-scientist. The candidate and his mentor have designed a training plan that will include a rigorous research component along with didactic instruction to establish the thought processes and principles necessary for successful career development. Acute lung Injury (ALI) and the more severe Acute Respiratory Distress Syndrome (ARDS) are diffuse lung diseases characterized by hypoxemia, capillary leakage, edema, and epithelial cell damage. These processes cause tremendous morbidity and mortality in the United States each year. Despite decades of research into the pathogenesis underlying the development of ALI, mortality remains high. There is a paucity of information known about the resolution phase of ALI;however, Regulatory T cells (Tregs) have been demonstrated to be important in ALI resolution in a mouse endotoxin (LPS) administration model of ALI. Furthermore, Tregs have been detected to increase in bronchoalveolar fluid of patients with ARDS, suggesting that they may be important in the human immunological response to ALI. In acute or chronic injury the failure to regenerate the lung epithelium plays a role in such processes as acute lung injury, pneumonia, pulmonary fibrosis, cancer, COPD, and aging. Recently there has been considerable interest in investigating the cells types involved in repair along with the determinants which regulate these processes. The candidate has preliminary data demonstrating that the presence or absence of Tregs modulates alveolar epithelial repair. This novel finding of Treg modulation of the alveolar epithelium has not been previously described. The focus of this proposal is to further examine Treg effects on the alveolar epithelium during ALI resolution with the hope of identifying novel mechanisms that may lead to potential treatment options in patients with ALI.
The specific aims proposed will utilize both in vivo and in vitro techniques to study Treg-alveolar epithelium interactions.
In Specific Aim 1, examination of the effect of Tregs on the alveolar epithelial barrier during ALI resolution will be performed alon with evaluation of the alveolar epithelium using multi-color flow cytometry and immunohistochemistry to quantify in vivo epithelial changes.
In Specific Aim 2, the impact Tregs exert on alveolar epithelial properties of phenotype and function will be determined through in vitro co-cultures of type II alveolar epithelial cells and Tregs. These experiments will explore new observations concerning Treg modulation of the alveolar epithelium during ALI with the ultimate goal of improving patient outcomes in this oftentimes fatal disease.

Public Health Relevance

Acute lung injury (ALI) is a common pulmonary disease with high morbidity and mortality. Regulatory T Cells (Tregs) have been shown to be important in the resolution of ALI but their potential interaction and modulation of the alveolar epithelium in damage and repair is unknown. We propose to study Treg modulation of alveolar epithelial cells with the hope of identifying novel mechanisms that may ultimately lead to new therapeutic options for this disease.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Postdoctoral Individual National Research Service Award (F32)
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Special Emphasis Panel (ZRG1-F10A-S (20))
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Colombini-Hatch, Sandra
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Johns Hopkins University
Internal Medicine/Medicine
Schools of Medicine
United States
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Mock, Jason R; Kolb, Todd M; Illei, Peter B et al. (2016) Bronchus-associated Lymphoid Tissue in Kabuki Syndrome with Associated Hyper-IgM Syndrome/Common Variable Immunodeficiency. Am J Respir Crit Care Med 194:514-5
Singer, Benjamin D; Mock, Jason R; D'Alessio, Franco R et al. (2016) Flow-cytometric method for simultaneous analysis of mouse lung epithelial, endothelial, and hematopoietic lineage cells. Am J Physiol Lung Cell Mol Physiol 310:L796-801
Limjunyawong, Nathachit; Mock, Jason; Mitzner, Wayne (2015) Instillation and Fixation Methods Useful in Mouse Lung Cancer Research. J Vis Exp :e52964
Singer, Benjamin D; Mock, Jason R; Aggarwal, Neil R et al. (2015) Regulatory T cell DNA methyltransferase inhibition accelerates resolution of lung inflammation. Am J Respir Cell Mol Biol 52:641-52
Kolb, Todd M; Peabody, Jacelyn; Baddoura, Philip et al. (2015) Right Ventricular Angiogenesis is an Early Adaptive Response to Chronic Hypoxia-Induced Pulmonary Hypertension. Microcirculation 22:724-36
Mock, J R; Garibaldi, B T; Aggarwal, N R et al. (2014) Foxp3+ regulatory T cells promote lung epithelial proliferation. Mucosal Immunol 7:1440-51
Garibaldi, Brian T; D'Alessio, Franco R; Mock, Jason R et al. (2013) Regulatory T cells reduce acute lung injury fibroproliferation by decreasing fibrocyte recruitment. Am J Respir Cell Mol Biol 48:35-43