Idiopathic pulmonary fibrosis (IPF) is a progressive, debilitating, and ultimately fatal disease for which no effective therapy exists. Recent research has focused on mechanisms that regulate activation of fibroblasts, the cell responsible for excessive matrix protein secretion and fibrosis. Interestingly, a cellular isoform of the matrix protein fibronectin (cellular fibronectin;cFn), termed EIIIA cFn, is deposited prior to the development of fibrosis and is essential for fibroblast activation through integrin receptor signaling. Fibroblast activation also relies on decreased levels and/or activity of an intracellular phosphatase called PTEN, which induces EIIIA cFn production. Thus, this proposal will focus on the hypothesis that decreased levels and/or activity of PTEN induces EIIIA cFn production which promotes and amplifies fibroblast activation. Experiments outlined in this application will define the mechanism by which PTEN regulates fibroblast activation in vitro and in vivo. Among the questions to be addressed are: 1) How does PTEN regulate EIIIA cFn expression? (i.e. what intracellular mechanisms regulate EIIIA cFn production when PTEN is inhibited?) 2) How does EIIIA cFn influence fibroblast behavior, and which integrin receptors are involved? 3) Can fibroblast activation, and subsequent pulmonary fibrosis, be attenuated when EIIIA cFn binding by fibroblasts is blocked in vivo? 4) Can fibroblast activation and fibrosis be made to occur when adding EIIIA cFn back to an in vivo system lacking EIIIA fibronectin? The relevance of this research is to define, in a mechanistic fashion, the series of events that leads to inappropriate scar tissue formation (fibrosis) in the lungs. The studies outlined in this proposal will specifically address how lung injury progresses to fibrosis and whether experimental lung fibrosis can be prevented or reversed. Successful completion of these experiments may also identify novel, potentially therapeutic, agents to combat lung fibrosis.
| Blue, Elizabeth E; Bis, Joshua C; Dorschner, Michael O et al. (2018) Genetic Variation in Genes Underlying Diverse Dementias May Explain a Small Proportion of Cases in the Alzheimer's Disease Sequencing Project. Dement Geriatr Cogn Disord 45:1-17 |
| Robinson-Cohen, Cassianne; Bartz, Traci M; Lai, Dongbing et al. (2018) Genetic Variants Associated with Circulating Fibroblast Growth Factor 23. J Am Soc Nephrol 29:2583-2592 |
| Cui, Chendi; Sekikawa, Akira; Kuller, Lewis H et al. (2018) Aortic Stiffness is Associated with Increased Risk of Incident Dementia in Older Adults. J Alzheimers Dis 66:297-306 |
| Ginsberg, Charles; Katz, Ronit; de Boer, Ian H et al. (2018) The 24,25 to 25-hydroxyvitamin D ratio and fracture risk in older adults: The cardiovascular health study. Bone 107:124-130 |
| Hammond, Christa A; Blades, Natalie J; Chaudhry, Sarwat I et al. (2018) Long-Term Cognitive Decline After Newly Diagnosed Heart Failure: Longitudinal Analysis in the CHS (Cardiovascular Health Study). Circ Heart Fail 11:e004476 |
| Liu, C; Marioni, R E; Hedman, Å K et al. (2018) A DNA methylation biomarker of alcohol consumption. Mol Psychiatry 23:422-433 |
| Ward-Caviness, Cavin K; Huffman, Jennifer E; Everett, Karl et al. (2018) DNA methylation age is associated with an altered hemostatic profile in a multiethnic meta-analysis. Blood 132:1842-1850 |
| Bhambhani, Vijeta; Kizer, Jorge R; Lima, Joao A C et al. (2018) Predictors and outcomes of heart failure with mid-range ejection fraction. Eur J Heart Fail 20:651-659 |
| Raghavan, Neha S; Brickman, Adam M; Andrews, Howard et al. (2018) Whole-exome sequencing in 20,197 persons for rare variants in Alzheimer's disease. Ann Clin Transl Neurol 5:832-842 |
| Austin, Thomas R; Wiggins, Kerri L; Blackshear, Chad et al. (2018) Atrial fibrillation in an African-American cohort: The Jackson Heart Study. Clin Cardiol 41:1049-1054 |
Showing the most recent 10 out of 355 publications
