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Adaptation to Hypoxia Program


Adaptation to Hypoxia Program (established in 1975) is currently the longest running Program Project Grant (PPG) in the Lung Division at the NIH/NHLBI. Part of the success of the 40 plus years of this program owes to the fact that it has continuously evolved since its inception. The program thrives on bringing together the best scientific expertise to pursue the most cutting edge investigations in the field, building on novel and exciting findings of its investigators and of the pulmonary vascular community in general. The current focus is how to address the role of inflammation and more specifically the role of macrophages in the vascular remodeling that characterizes the most frequent forms of chronic pulmonary hypertension (PH). Our Program focuses frontally on inflammation as one of the key pathogenetic features of PH as defined in the 2013 World Symposium on Pulmonary Hypertension in Nice. Importantly, this requires the careful consideration of the clinical, pathological, and possibly pathobiological heterogeneity of PH, which is manifested by its complex classification. As apparent through the scope of the projects and the overall infrastructure of this Program, we are poised to provide novel insights into the complex cellular and molecular pathophysiology of inflammation in various forms of PH, hopefully leading to identification of translatable new therapeutic approaches for human forms of the disease. Our investigations will ultimately provide key data in elucidating the role of inflammation as a cause/contributor, a bystander, or whether and when it is simply the end result of the disease process, a critical step to advance our understanding of chronic pulmonary vascular disease in order to significantly impact the clinical management of PH.
A major strength of this Program is that we bring together a powerful and diverse group of investigators from the University of Colorado Denver, National Jewish Hospital, and from Stanford University who have made seminal contributions in identifying and defining the role of macrophages in chronic PH of various etiologies. Dr. Kurt R. Stenmark, MD (CVP director and main PI) is working on Crosstalk Between Metabolism and Inflammation in Pulmonary Hypertension. Drs. Karim El Kasmi and Quinghong Zhang bring their deep understanding and research discoveries in macrophage biology and metabolic signaling in cancer, respectively.
Dr. Rubin Tuder, MD is focusing on Role of Inflammation in Schistosomiasis Pulmonary Hypertension. Dr. Tuder is also a world class expert in pulmonary vascular pathology and pathobiology and he runs the Pathology, Imaging, and Flow Cytometry Core.
Dr. Tuder and his colleagues bring a high level of expertise, gained over two decades of investigation in pulmonary vascular disease, inflammation and fibrosis. Dr. Brian Graham, MD is working very closely with Dr. Tuder, together they have led this area of investigation, having published seminal papers describing the role of the macrophage and specifically TGFb in a schistosomiasis model of PH. This exciting model system not only allows detailed investigation of mechanisms directly related to the most common cause of PH in the world but also seems to have relevance to other forms of Class I PH, especially SSc PH.
Dr. Mark Nicolls, MD (Stanford University) is working on The Role of Macrophage-Derived Leukotriene B4 (LTB4) in Pulmonary Hypertension. Dr. Nicolls is closely collaborating with Dr. Peter Henson, PhD from National Jewish Health (Denver, CO), an investigator with a long and illustrious history of contributions regarding macrophage and eicosanoid biology to lung disease, including extensive previous collaboration with the Project PIs. Dr. Nicolls is a transplant immunologist, who during his tenure at the University of Colorado developed an interest in the inflammation observed in patients and experimental animals with PH. His recent studies in Circulation Research (4) and Science Translational Medicine (5) demonstrate the key role of macrophages in yet another model of PH, the immunocompromised rats. He has identified a key role for LTB4 production by the macrophages in the PH process. This focus on leukotriene biology provides insights into the role of leukotrienes in PH, which incidentally was the focus of Dr. Stenmark’s first project in the PPG almost 30 years ago.
The program and its investigators also utilize the unique expertise and experience of many other investigators at the University of Colorado, Stanford University, and at other institutions both within and outside of the United States. Mark Geraci, MD and Todd Bull, MD are running PPG Clinical Core. This Core integrates translational studies with the work being done in animal systems. Our Program have nearly unmatched access to the human tissues from the PH Breakthrough Initiative (PHBI).
Dr. David Irwin is directing the Animal and Hemodynamics Core – see more details in Animal Core tab.