Endothelium lines blood vessels, and inter-connects all organ systems. There has been a growing appreciation that endothelial cells exhibit a rich diversity in structure and function. Such heterogeneity is apparent between endothelial cells in different organs, in endothelial cells along a single vascular segment within an organ and, indeed, between immediately adjacent cells. In the pulmonary circulation, endothelium in extra-alveolar blood vessels differs markedly from those in capillary segments. This program project grant is founded on the overall hypothesis that endothelium lining pulmonary arteries, capillaries, and veins is phenotypically distinct;each cell type is highly specialized to fulfill he unique demands of its vascular niche. We possess a limited understanding of how such heterogeneity is achieved to control site specific vascular demands, particularly in the lung's microvascular compartment. A principal goal in this amended renewal application is therefore to rigorously determine molecular mechanisms that allow lung microvascular endothelial cells to successfully control capillary function. Moreover, lung microvascular endothelial cell function is impaired by bacteria, such as Pseudomonas aeruginosa, during infection that culminates in acute lung injury. Hence, pulmonary microvascular endothelium represents a putative therapeutic target to combat vascular dysfunction in acute lung injury. The three projects in this amended renewal systematically study mechanisms regulating endothelial cell permeability and neutrophil transmigration;each project addresses three specific objectives, to: (1) identify and test novel molecular mechanisms (e.g. signatures) that control site-specific endothelial cell function, especially focusing on the microcirculation, (2) determine the importance of these mechanisms in preclinical models of disease, and (3) translate novel therapeutic approaches in preclinical models of disease. Projects are highly interactive both conceptually and pragmatically. This Program Project Grant draws on emerging developments in different fields of study, and applies these developments to generate new information about how microvascular endothelial cells, in particular, respond to inflammation and how they repair following injury. Defining the mechanisms that underlie lung microvascular endothelial cell function will provide insight into the site-specific nature of pulmonary vascular disease, and allow us to ultimately develop rational pharmacological therapies to discretely intervene in endothelial cell dysfunction that occurs in all known pulmonary vascular diseases.
Endothelial cells line all blood vessels in the body, and coordinate the communication that occurs between the blood and tissues. Endothelial cell injury or dysfunction is a cardinal feature of vascular disease, making the endothelium an important therapeutic target. However, endothelial cells behave differently along blood vessels, and the molecules responsible for these distinct behaviors may represent key signatures of a vascular location, and novel targets for therapy, each principal goals of this program project grant.
|Leavesley, Silas J; Walters, Mikayla; Lopez, Carmen et al. (2016) Hyperspectral imaging fluorescence excitation scanning for colon cancer detection. J Biomed Opt 21:104003|
|Spadafora, Domenico; Kozhukhar, Natalia; Alexeyev, Mikhail F (2016) Presequence-Independent Mitochondrial Import of DNA Ligase Facilitates Establishment of Cell Lines with Reduced mtDNA Copy Number. PLoS One 11:e0152705|
|Alvarez, Diego F; Housley, Nicole; Koloteva, Anna et al. (2016) Caspase-1 Activation Protects Lung Endothelial Barrier Function during Infection-Induced Stress. Am J Respir Cell Mol Biol 55:500-510|
|Morrow, K Adam; Ochoa, Cristhiaan D; Balczon, Ron et al. (2016) Pseudomonas aeruginosa exoenzymes U and Y induce a transmissible endothelial proteinopathy. Am J Physiol Lung Cell Mol Physiol 310:L337-53|
|Blair, Leslie A; Haven, April K; Bauer, Natalie N (2016) Circulating microparticles in severe pulmonary arterial hypertension increase intercellular adhesion molecule-1 expression selectively in pulmonary artery endothelium. Respir Res 17:133|
|Jian, Ming-Yuan; Liu, Yanping; Li, Qian et al. (2016) N-cadherin coordinates AMP kinase-mediated lung vascular repair. Am J Physiol Lung Cell Mol Physiol 310:L71-85|
|Shetewy, Aza; Shimada-Takaura, Kayoko; Warner, Danielle et al. (2016) Mitochondrial defects associated with Î²-alanine toxicity: relevance to hyper-beta-alaninemia. Mol Cell Biochem 416:11-22|
|Shokolenko, Inna N; Wilson, Glenn L; Alexeyev, Mikhail F (2016) The "fast" and the "slow" modes of mitochondrial DNA degradation. Mitochondrial DNA A DNA Mapp Seq Anal 27:490-8|
|Kozhukhar, Natalya; Spadafora, Domenico; Fayzulin, Rafik et al. (2016) The efficiency of the translesion synthesis across abasic sites by mitochondrial DNA polymerase is low in mitochondria of 3T3 cells. Mitochondrial DNA A DNA Mapp Seq Anal 27:4390-4396|
|Nguyen, Joanne M; Qualmann, Krista J; Okashah, Rebecca et al. (2015) 5p deletions: Current knowledge and future directions. Am J Med Genet C Semin Med Genet 169:224-38|
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