Pulmonary hypertension and pseumonectomy are examples of pulmonary conditions that implicate mechanical stress as a stimulus for lung cell proliferation and extracellular matrix production. In the present study, calcyclin gene expression is proposed to be an essential event in the mechanotransduction pathway signaling new cell division. More specifically, calcyclin is thought to function as a regulatory protein controlling changes in cell shape and cytoskeletal organization required for the cell cycle to progress. To test this hypothesis an isolated-perfused lung model of increased mechanical strain will be used to correlate the level and location of calcyclin and related lung S100 gene expression with pulmonary cell proliferation. Calcyclin and S100 gene expression will also be measured in fibroblasts stimulated to proliferate in response to mechanical skeletal organization and cell shape. Cytoskeletal involvement will be confirmed by measuring calcyclin levels in the cytoskeletal subcellular fraction and association with tropomyosin. Furthermore, transcriptional activation via cis-acting promoter elements and PDGF autocrine activity will be tested as possible regulatory control steps in this pathway. Pulmonary fibroblasts are also proposed to play an important role in strain-induced ECM remodeling. Therefore, 1) Total pro-collagen and tropoelastin synthesis will be measured in isolated perfused rat lungs ventilated at high or low states of lung inflation 2) The gene expression of a1 (I) pro-collagen and tropoelastin will be measured in mechanically strained fibroblasts cultured on ECM proteins (fibronectin elastin, laminin( 3) The role of cell shape and cytoskeletal organization will be analyzed by disruption of microfilaments, microtubules or intermediate filaments; estimating the number of ECM- cell contact sites; and identifying the abundance and specificity of ECM receptors (integrins) present on the cell surface. The functional role of specific ECM-fibroblast interactions will be determined by inhibition with fibronectin, laminin, or elastin peptides. 4) Finally, the ability of ECM peptide ligands to down regulate strain induced pro-collagen and tropoelastin expression will be tested in our mechanical strain lung model. This research will give further insight into possible strain induced proliferation and ECM remodeling observed in several physiological models currently under investigation in our integrative respiratory physiology division.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL017731-28
Application #
6589834
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
2002-05-01
Project End
2003-04-30
Budget Start
Budget End
Support Year
28
Fiscal Year
2002
Total Cost
$246,248
Indirect Cost
Name
University of California San Diego
Department
Type
DUNS #
077758407
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Richardson, Russell S; Wary, Claire; Wray, D Walter et al. (2015) MRS Evidence of Adequate O? Supply in Human Skeletal Muscle at the Onset of Exercise. Med Sci Sports Exerc 47:2299-307
Esposito, F; Wagner, P D; Richardson, R S (2015) Incremental large and small muscle mass exercise in patients with heart failure: evidence of preserved peripheral haemodynamics and metabolism. Acta Physiol (Oxf) 213:688-99
Olfert, I Mark; Malek, Moh H; Eagan, Tomas M L et al. (2014) Inflammatory cytokine response to exercise in alpha-1-antitrypsin deficient COPD patients 'on' or 'off' augmentation therapy. BMC Pulm Med 14:106
Poole, David C; Copp, Steven W; Ferguson, Scott K et al. (2013) Skeletal muscle capillary function: contemporary observations and novel hypotheses. Exp Physiol 98:1645-58
Koga, S; Wüst, R C I; Walsh, B et al. (2013) Increasing temperature speeds intracellular PO2 kinetics during contractions in single Xenopus skeletal muscle fibers. Am J Physiol Regul Integr Comp Physiol 304:R59-66
Breen, Ellen C; Malloy, Jaret L; Tang, Kechun et al. (2013) Impaired pulmonary defense against Pseudomonas aeruginosa in VEGF gene inactivated mouse lung. J Cell Physiol 228:371-9
Tang, Kechun; Murano, George; Wagner, Harrieth et al. (2013) Impaired exercise capacity and skeletal muscle function in a mouse model of pulmonary inflammation. J Appl Physiol 114:1340-50
Wray, D Walter; Nishiyama, Steven K; Donato, Anthony J et al. (2011) The paradox of oxidative stress and exercise with advancing age. Exerc Sport Sci Rev 39:68-76
Esposito, Fabio; Mathieu-Costello, Odile; Shabetai, Ralph et al. (2010) Limited maximal exercise capacity in patients with chronic heart failure: partitioning the contributors. J Am Coll Cardiol 55:1945-54
Esposito, Fabio; Mathieu-Costello, Odile; Entin, Pauline L et al. (2010) The skeletal muscle VEGF mRNA response to acute exercise in patients with chronic heart failure. Growth Factors 28:139-47

Showing the most recent 10 out of 382 publications