While endothelium has historically been considered a homogeneous cell layer, there is an increasing appreciation that it exhibits a rich diversity in structure and function. 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. This Program Project Grant is founded on the hypothesis that endothelium lining the lung's extra-alveolar and alveolar blood vessels is phenotypically distinct, and that the unique behavior(s) of cells from these different vascular locations is necessary for them to fulfill their sitespecific function(s). We currently 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 competitive renewal application is therefore to rigorously determine molecular mechanisms that allow lung microvascular endothelial cells to successfully control their capillary function. Our focus on the microvascular endothelial cell phenotype is based upon the relative paucity of information regarding the behavior of this cell type. We propose four inter-related projects examining different signal transduction cascades that control lung microvascular endothelial cell behavior, including permeability regulation (Stevens, Project 1 and Townsley, Project 4), apoptosis/necrosis (Gillespie, Project 2), and von Willebrand factor secretion (Wu, Project 3). These projects are highly interactive both conceptually and pragmatically. Toward this end, this Program Project Grant draws on emerging developments in different fields of study, and applies these developments to generate new information about how microvascular lung 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 the endothelial cell dysfunction that occurs in all known pulmonary vascular diseases.
| Khozhukhar, Natalya; Spadafora, Domenico; Rodriguez, Yelitza et al. (2018) Elimination of Mitochondrial DNA from Mammalian Cells. Curr Protoc Cell Biol 78:20.11.1-20.11.14 |
| Leavesley, Silas J; Sweat, Brenner; Abbott, Caitlyn et al. (2018) A theoretical-experimental methodology for assessing the sensitivity of biomedical spectral imaging platforms, assays, and analysis methods. J Biophotonics 11: |
| Lin, Mike T; Balczon, Ron; Pittet, Jean-Francois et al. (2018) Nosocomial Pneumonia Elicits an Endothelial Proteinopathy: Evidence for a Source of Neurotoxic Amyloids in Critically Ill Patients. Am J Respir Crit Care Med : |
| Parker, James C (2018) Mitochondrial damage pathways in ventilator induced lung injury (VILI): an update. J Lung Health Dis 2:18-22 |
| Balczon, Ron; Morrow, K Adam; Zhou, Chun et al. (2017) Pseudomonas aeruginosa infection liberates transmissible, cytotoxic prion amyloids. FASEB J 31:2785-2796 |
| Shokolenko, Inna N; Alexeyev, Mikhail F (2017) Mitochondrial transcription in mammalian cells. Front Biosci (Landmark Ed) 22:835-853 |
| Morrow, K Adam; Frank, Dara W; Balczon, Ron et al. (2017) The Pseudomonas aeruginosa Exoenzyme Y: A Promiscuous Nucleotidyl Cyclase Edema Factor and Virulence Determinant. Handb Exp Pharmacol 238:67-85 |
| 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 |
| Leavesley, Silas J; Rich, Thomas C (2016) Overcoming limitations of FRET measurements. Cytometry A 89:325-7 |
Showing the most recent 10 out of 122 publications
