This proposal describes a 5-year training program which will allow the principal investigator to develop an academic career in Pulmonary Medicine. The principal investigator has completed a structured residency training program in Internal Medicine and fellowship training in Pulmonary and Critical Care Medicine, and will now utilize a unique combination of environment and collaborative opportunities to expand his scientific skills. The program will investigate schistosomiasis-associated pulmonary arterial hypertension (PAH), a parasitic disease which affects approximately 2-5 million people worldwide, primarily in Brazil and Africa. Dr. Rubin Tuder, a leader in the field of pulmonary vascular biology, will mentor the principal investigator's scientific development. Dr. Tuder is the Director of Research in the Pulmonary-Critical Care Medicine Division at the University of Colorado Denver. Other collaborators include Dr. Thomas Wynn, a renowned immunopathologist at the NIH and Dr. Kurt Stenmark, an expert in experimental PAH at UC Denver. Our overall research goal is to elucidate how the host response to Schistosoma mansoni results in PAH. Most rodent models of experimental pulmonary hypertension (PH) employ either chronic hypoxia or endothelial cell toxicity with monocrotaline, but such stimuli do not accurately model the inflammatory pathways likely contributory to the pathogenesis of potentially all forms of severe PAH. Schistosomiasis-associated PAH may involve the direct interplay of inflammatory cells and cytokines with signaling pathways that control pulmonary vascular remodeling. Our experiments will use mice infected with the parasite, resulting in PH. We hypothesize inflammation is linked with vascular remodeling by the IL-4/IL-13/RELM-1 and TGF-2/Smad2/3 pathways. We have observed IL-13 signaling upregulation is adequate to worsen S. mansoni-associated PH, and the TGF-2 signaling target p-Smad2/3 is increased in pathologic pulmonary vessels in both infected mice and humans.
Our specific aims are to determine if (1) IL-4/IL-13 and (2) TGF-2 signaling are necessary for Schistosoma- induced PH. We will use exogenous inhibitors and knockout mouse lines to modulate IL-4, IL-13 and TGF-2 function, and analyze pulmonary hemodynamics, pulmonary vascular remodeling, and inflammatory signaling. Determining the mechanism by which schistosomiasis infection leads to vascular remodeling will (1) provide insight into the interplay between pulmonary vascular inflammation and remodeling, which also participates in the pathogenesis of other forms of PAH, and (2) demonstrate opportunities for therapeutic intervention in schistosomiasis-associated PAH and other forms of inflammatory PAH. The Pulmonary-Critical Care Division at the University of Colorado Denver is an ideal setting for training physician-scientists through the incorporation of expertise from many resources into a customized training program. The environments at the level of the University, Division, and Advisory Committees are all optimally aligned for the success of the project and for the career development of the principal investigator.

Public Health Relevance

Schistosomiasis is the third most common parasitic disease worldwide and one of the most common causes of pulmonary arterial hypertension (PAH), a devastating condition of progressive shortness of breath and heart failure. How schistosomiasis causes PAH is unknown. We are studying mice infected with schistosomiasis to determine why the disease occurs and provide insight into treatment possibilities for schistosomiasis, schistosomiasis-associated PAH, and other causes of PAH more common in developed countries.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08HL105536-03
Application #
8505024
Study Section
Special Emphasis Panel (ZHL1-CSR-K (M4))
Program Officer
Colombini-Hatch, Sandra
Project Start
2011-07-01
Project End
2016-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
3
Fiscal Year
2013
Total Cost
$130,658
Indirect Cost
$8,908
Name
University of Colorado Denver
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
Graham, Brian B; Robinson, Jeffrey C; Tuder, Rubin M (2016) Fatty Acid Metabolism, Bone Morphogenetic Protein Receptor Type 2, and the Right Ventricle. Am J Respir Crit Care Med 194:655-6
Graham, Brian B; Kumar, Rahul; Mickael, Claudia et al. (2015) Severe pulmonary hypertension is associated with altered right ventricle metabolic substrate uptake. Am J Physiol Lung Cell Mol Physiol 309:L435-40
Kumar, Rahul; Mickael, Claudia; Chabon, Jacob et al. (2015) The Causal Role of IL-4 and IL-13 in Schistosoma mansoni Pulmonary Hypertension. Am J Respir Crit Care Med 192:998-1008
Robinson, Jeffrey C; Graham, Brian B; Rouault, Tracey C et al. (2014) The crossroads of iron with hypoxia and cellular metabolism. Implications in the pathobiology of pulmonary hypertension. Am J Respir Cell Mol Biol 51:721-9
El Kasmi, Karim C; Pugliese, Steven C; Riddle, Suzette R et al. (2014) Adventitial fibroblasts induce a distinct proinflammatory/profibrotic macrophage phenotype in pulmonary hypertension. J Immunol 193:597-609
Bertero, Thomas; Lu, Yu; Annis, Sofia et al. (2014) Systems-level regulation of microRNA networks by miR-130/301 promotes pulmonary hypertension. J Clin Invest 124:3514-28
Nadon, Aaron M; Perez, Mario J; Hernandez-Saavedra, Daniel et al. (2014) Rtp801 suppression of epithelial mTORC1 augments endotoxin-induced lung inflammation. Am J Pathol 184:2382-9
Graham, Brian B; Kumar, Rahul (2014) Schistosomiasis and the pulmonary vasculature (2013 Grover Conference series). Pulm Circ 4:353-62
Stearman, Robert S; Cornelius, Amber R; Lu, Xiao et al. (2014) Functional prostacyclin synthase promoter polymorphisms. Impact in pulmonary arterial hypertension. Am J Respir Crit Care Med 189:1110-20
Chabon, Jacob J; Gebreab, Liya; Kumar, Rahul et al. (2014) Role of vascular endothelial growth factor signaling in Schistosoma-induced experimental pulmonary hypertension. Pulm Circ 4:289-99

Showing the most recent 10 out of 20 publications