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.
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.
|Kumar, Rahul; Mickael, Claudia; Kassa, Biruk et al. (2017) TGF-? activation by bone marrow-derived thrombospondin-1 causes Schistosoma- and hypoxia-induced pulmonary hypertension. Nat Commun 8:15494|
|Ali, Zahara; Kosanovic, Djuro; Kolosionek, Ewa et al. (2017) Enhanced inflammatory cell profiles in schistosomiasis-induced pulmonary vascular remodeling. Pulm Circ 7:244-252|
|Graham, Brian B; Koyanagi, Dan; Kandasamy, Balasubramaniyam et al. (2017) Right Ventricle Vasculature in Human Pulmonary Hypertension Assessed by Stereology. Am J Respir Crit Care Med 196:1075-1077|
|Pugliese, Steven C; Kumar, Sushil; Janssen, William J et al. (2017) A Time- and Compartment-Specific Activation of Lung Macrophages in Hypoxic Pulmonary Hypertension. J Immunol 198:4802-4812|
|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|
|Bertero, Thomas; Cottrill, Katherine A; Lu, Yu et al. (2015) Matrix Remodeling Promotes Pulmonary Hypertension through Feedback Mechanoactivation of the YAP/TAZ-miR-130/301 Circuit. Cell Rep 13:1016-32|
|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|
|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|
|White, Kevin; Lu, Yu; Annis, Sofia et al. (2015) Genetic and hypoxic alterations of the microRNA-210-ISCU1/2 axis promote iron-sulfur deficiency and pulmonary hypertension. EMBO Mol Med 7:695-713|
|Graham, Brian B; Kumar, Rahul (2014) Schistosomiasis and the pulmonary vasculature (2013 Grover Conference series). Pulm Circ 4:353-62|
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