This application seeks renewal of a program that is now in its 35th year. The proposal comprises four scientific projects focused on studies of the mechanisms of hypoxic pulmonary hypertension (PH). The proposed studies are collectively founded on the hypothesis that the pathogenesis of hypoxic PH involves both functional (vasoconstriction and wall stiffening) and structural (vascular wall thickening) components, and that both components involve hypoxia-induced alterations in resident cell function as well as recruitment and interactions with inflammatory and/or progenitor cells. Projects 1, and 3 represent continuation and evolution of current program projects, while Projects 2 and 4 have been added to incorporate complementary new directions and expertise. The projects are highly interactive, both conceptually and in the performance and communication of experimental results, share numerous models and techniques, and are supported by three strong cores: administrative, animal, and tissue. The project leaders, Drs. Stenmark, Nemenoff, Klemm and Geraci have worked together on studies regarding cell signalling and of pulmonary hypertension for many years. The four projects address new and innovative hypotheses regarding the cellular mechanisms of chronic hypoxic PH. Project 1 explores the role of circulating myeloid mesenchymal progenitor cells, fibrocytes, in vascular remodeling and stiffening. Project 2 proposes that the phosphatase PTEN is a potent, endogenously produced inhibitor of SM proliferation and that SM-specific PTEN inactivation is an early and critical trigger driving vascular remodeling. Project 3 investigates how loss of CREB in SMC results in increases in SM proliferation, collagen elastin synthesis and VCAM-1 expression, which ultimately leads to accumulation of monocytes/progenitor cells and remodeling in the pulmonary arterial wall. Project 4 examines the role of disrupted PGI2 and PPAR? signaling in the aberrent cell growth characterizing chronic pulmonary vascular remodeling. These studies will provide new insights into the cellular/molecular mechanisms of chronic hypoxic pulmonary vasoconstriction and vascular stiffening and remodeling and may lead to novel, more effective therapy for hypoxic PH.
Pulmonary hypertension (PH) complicates the clinical course of many chronic heart and lung diseases. Its'presence significantly increases the morbidity and mortality of the underlying disease. Current treatments are non-specific and often unsuccessful because mechanisms leading to the development of PH remain unclear. Our goal is to better understand the disease process, ultimately allowing for successful intervention.
|Cohrs, Randall J; Lee, Katherine S; Beach, Addilynn et al. (2017) Targeted Genome Sequencing Reveals Varicella-Zoster Virus Open Reading Frame 12 Deletion. J Virol 91:|
|Lapel, Martin; Weston, Philip; Strassheim, Derek et al. (2017) Glycolysis and oxidative phosphorylation are essential for purinergic receptor-mediated angiogenic responses in vasa vasorum endothelial cells. Am J Physiol Cell Physiol 312:C56-C70|
|Lin, Y-C; Sung, Y K; Jiang, X et al. (2017) Simultaneously Targeting Myofibroblast Contractility and Extracellular Matrix Cross-Linking as a Therapeutic Concept in Airway Fibrosis. Am J Transplant 17:1229-1241|
|Tuder, Rubin M (2017) Pulmonary vascular remodeling in pulmonary hypertension. Cell Tissue Res 367:643-649|
|Loomis, Zoe; Eigenberger, Paul; Redinius, Katherine et al. (2017) Correction: Hemoglobin induced cell trauma indirectly influences endothelial TLR9 activity resulting in pulmonary vascular smooth muscle cell activation. PLoS One 12:e0173652|
|Murakami, A; Wang, L; Kalhorn, S et al. (2017) Context-dependent role for chromatin remodeling component PBRM1/BAF180 in clear cell renal cell carcinoma. Oncogenesis 6:e287|
|de Bourcy, Charles F A; Dekker, Cornelia L; Davis, Mark M et al. (2017) Dynamics of the human antibody repertoire after B cell depletion in systemic sclerosis. Sci Immunol 2:|
|Cree-Green, Melanie; Gupta, Abhinav; Coe, Gregory V et al. (2017) Insulin resistance in type 2 diabetes youth relates to serum free fatty acids and muscle mitochondrial dysfunction. J Diabetes Complications 31:141-148|
|Jansing, Nicole L; McClendon, Jazalle; Henson, Peter M et al. (2017) Unbiased Quantitation of Alveolar Type II to Alveolar Type I Cell Transdifferentiation during Repair after Lung Injury in Mice. Am J Respir Cell Mol Biol 57:519-526|
|Loomis, Zoe; Eigenberger, Paul; Redinius, Katherine et al. (2017) Hemoglobin induced cell trauma indirectly influences endothelial TLR9 activity resulting in pulmonary vascular smooth muscle cell activation. PLoS One 12:e0171219|
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