Principal Investigator: Ana L. Mora, MD
Associate Professor of Medicine,
Division of Pulmonary, Allergy and Critical Care Medicine
200 Lothrop Street
Pittsburgh, PA 15261
Office Phone: 412-624-2291
Lab Phone: 412-624-2132
Ana Mora received her MD from the National University of Colombia. She then completed a fellowship in Immunology at the Institute of Immunology and the Department of Microbiology and Immunology at Vanderbilt University.Her postdoctoral training research was completed in the laboratory of James P. Tam PhD., and Mark Boothby MD, PhD. Dr. Mora has held research grants from the National Institutes of Health, the American Lung Association, the American Heart Association, and the Aging Institute at the University of Pittsburgh. Dr. Mora’s honors include the Sidney P. Colowick award, Scholar from the McKelvey Lung Transplantion Center -Emory University, and recognitions from the American Association of Immunologists, the Pulmonary Fibrosis Foundation, and by the Institute of Lung Biology and Disease, Comprehensive Pneumology Center at Munich, Germany.
Dr. Mora’s research is focused in the understanding of the pathogenesis of idiopathic Pulmonary Fibrosis (IPF), a fatal and progressive lung disease, characterized by progressive scarring of the lung. IPF prevalence dramatically increases with age, and aging is a known risk factor for IPF. However, there is limited understanding in the mechanisms involved in the increased vulnerability of the aging lung to develop lung fibrosis. Our research utilizes a combination of novel animal models with genetically altered mice and samples from human subjects. Our published findings were pioneered to identify alterations in mitochondrial homeostasis in the aging type alveolar epithelial cell (AECII) as a critical component of the pathogenesis of IPF. Currently, our studies are extending to other diseases characterized by abnormal tissue repair and exaggerated remodeling, including pulmonary hypertension (PH).
Fibrosis as a Disease of Aging and Mitochondrial Dysfunction
Despite the fact that Idiopathic Pulmonary Fibrosis (IPF) is a fatal and progressive lung disease of unknown etiology, few new patho-biologic models have emerged. Repetitive injury of mitochondrial-enriched type II alveolar epithelial cells (AECII) appears to be a key triggering event that leads to fibrosis, which is linked to a secretion of pro-fibrotic cytokines and increased apoptosis. Although AECII contain approximately 50% of the lung mitochondrial mass, the role of mitochondria in IPF pathobiology is unknown. We recently discovered that AECII from human IPF lungs have an accumulation of dysmorphic and dysfunctional mitochondria associated with very low expression of the crucial protective protein involved in mitochondrial homeostasis, PTEN-induced putative kinase 1 (PINK1). Low expression of PINK1 is associated with ER stress and aging, leading to increased susceptibility to cell apoptosis and fibrosis. However, no information is available how ER stress regulates PINK1 expression and how loss of PINK1 activates pro-fibrotic responses. Our novel studies suggest that the ER stress induces a transcriptional repressor that negatively regulates PINK1 gene expression, and reduced PINK1 levels. Low expression of PINK1 leads to mitochondrial depolarization, apoptosis, and release of damage associated molecular pattern that activate pro-fibrotic responses. Our studies bring forth a unique molecular model linking mitochondrial dysfunction and fibrosis that sets the stage for identifying novel links of aging and fibrosis and therapeutic targets.
Mitochondrial Homeostasis and Pulmonary Hypertension
Pulmonary arterial hypertension (PAH) is a disease characterized by increased pulmonary vascular resistance and mean pulmonary arterial pressure leading to dysfunction of the right ventricle, reduced cardiac output and death. Vascular remodeling is characterized by obstructive vascular lesions of the distal pulmonary arteries due in part to excessive injury and apoptosis of endothelial cells and proliferation of the pulmonary artery smooth muscle cells (PASMCs). Mitochondria dysregulation is intimately related with the etiology of PAH. We are investigating the potential role of dysregulated mitochondrial homeostasis in endothelial vulnerability to injury and PASMCs proliferation using unique animal models of PAH, novel hemodynamic assessments in rodents of pulmonary hypertension and heart function, and lung cells derived from PAH patients.
PINK1 and mtDNA metabolism
The mitochondrial genome is 16.5 kb and mechanisms to maintain their replication, translation, and repair are not completely understood. A reduction in mitochondrial DNA (mtDNA) replication and/or transcription may contribute to impaired mitochondrial oxidative phosphorylation, or accumulation of mtDNA mutations may affect mtDNA replication and transcription. We are studying in collaboration with Dr. Brett Kaufman whether PINK1 regulates mtDNA metabolism by regulation of TFAM, the principal packaging and key transcription factor of mtDNA, and the function of mtDNA repair enzymes.
Mora AL, Woods CR, Garcia A, Xu J, Rojas M, Speck SH, Roman J, Brigham KL, Stecenko AA. (2005) Lung infection with gamma-herpesvirus induces progressive pulmonary fibrosis in Th2-biased mice. Am J Physiol Lung Cell Mol Physiol. 289(5):L711-21. (PMID: 15734789)
- Editorial comment: Doran P and JJ Egan. Herpesviruses: a cofactor in the pathogenesis of idiopathic pulmonary fibrosis. 2005 Nov; 285(5):L709-L710.
Mora AL, Torres-Gonzalez E, Rojas M, Corredor C, Ritzenthaler J, Xu J, Roman J, Brigham K, Stecenko A. (2006) Activation of alveolar macrophages via the alternative pathway in herpesvirus-induced lung fibrosis. Am J Respir Cell Mol Biol. 35(4):466-73. (PMID: 16709958 / PMCID: PMC2643265)
Cover is based on an image showing accumulation of alveolar macrophages in fibrotic areas of MHV68-infected IFN-γR−/− mice— Masson trichrome staining from IFN-γR −/−mice at Day 180 after MHV68 infection. Mora AL. Am J Respir Cell and Mol Biol. 35(4):466-73.
Mora AL, Torres-Gonzalez E, Rojas M, Xu J, Ritzenthaler J, Speck SH, Roman J, Brigham K, Stecenko A. (2007) Control of virus reactivation arrests pulmonary herpesvirus-induced fibrosis in IFN-gamma receptor-deficient mice. Am J Respir Crit Care Med. 175(11):1139-50. (PMID 17363768 / PMCID PMC1899276)
- Comment in Am J Respir Crit Care Med. 175(11):1101-2.
Cover is based on an image of Masson trichrome staining of lung section from a murine γ-herpesvirus 68 (MHV68)–infected mouse. Mora AL. Am J Respir Crit Care Med. 175(11):1139-50.
Pozharskaya V, Torres-Gonzalez E, Rojas M, Gal A, Amin M, Dollard S, Roman J, Stecenko AA, Mora AL. (2009) Twist: a regulator of epithelial-mesenchymal transition in lung fibrosis. PLoS One. 4(10):e7559. (PMID 19851501/PMCID PMC2761603)
Krug LT, Torres-Gonzalez E, Qin Q, Sorescu D, Rojas M, Stecenko A, Speck SH, Mora AL. (2010) Inhibition of NF-kappaB signaling reduces virus load and gammaherpesvirus-induced pulmonary fibrosis. Am J Pathol. 177(2):608-21. (PMID 20566741/PMCID PMC2913377)
Mora AL, Rojas M. (2008) Aging and lung injury repair: a role for bone marrow derived mesenchymal stem cells. J Cell Biochem. 105(3):641-7. (PMID 18759327)
Torres-Gonzalez E, Bueno M, Tanaka A, Krug L, Cheng D-S, Sorescu D, Blackwell T, Rojas M, Mora AL (2012). Endoplasmic reticulum stress in age-related susceptibility to lung fibrosis. Am J Respir Cell Mol Biol. Jun; 46 (6). PMID: 22227563. PMCID: PMC3380287.
Bueno M, Lai Y-C, Romero Y, Brands J, StCroix C, Kamga C, Corey C, Herazo-Maya JD, Sembrant J, Lee J, Duncan SR, Rojas M, Shiva S, Chu CT, Mora AL. PINK1 deficiency impairs mitochondrial homeostasis and promotes lung fibrosis. J. Clin Invest.,2015. 125(2):521-38. PMID: 25562319.
Featured in JCI Impact
The cover image is a false-colored transmission electron micrograph of an alveolar type II cell from the lung of a patient with idiopathic pulmonary fibrosis. Dysmorphic, swollen mitochondria are shown in pink.
Lai Y-C, Tabima DM, Dube JJ, Hughan KS, Vanderpool RR, Goncharov D, St Croix CM, Garcia-Ocaña A, Goncharova EA, Tofovic SP, Mora AL, Gladwin MT. SIRT3-AMPK activation by nitrite and metformin improves hyperglycemia and normalizes pulmonary hypertension in heart failure with preserved ejection fraction (PH-HFpEF). Circulation. 2016. 133(8):717-31. PMID: 26813102.
Romero Y, Bueno M, Ramirez R, Álvarez D, Sembrat JC, Goncharova EA, Rojas M, Selman M, Mora AL, Pardo A. mTORC1 activation decreases autophagy in aging and idiopathic pulmonary fibrosis and contributes to apoptosis resistance in IPF fibroblasts. Aging Cell. 2016 Aug 26. doi: 10.1111/acel.12514.
Kelly NJ, Radder JE, Baust JJ, Burton CL, Lai YC, Potoka KC, Agostini BA, Wood JP, Bachman TN, Vanderpool RR, Dandachi N, Leme AS, Gregory AD, Morris A, Mora AL, Gladwin MT, Shapiro SD. Mouse Genome-Wide Association Study of Preclinical Group II Pulmonary Hypertension Identifies Epidermal Growth Factor Receptor. Am J Respir Cell Mol Biol. 2017 Apr;56(4):488-496.
Meng Q, Lai YC, Kelly NJ, Bueno M, Baust JJ, Bachman TN, Goncharov D, Vanderpool RR, Radder JE, Hu J, Goncharova E, Morris AM, Mora AL, Shapiro SD, Gladwin MT. Development of a Mouse Model of Metabolic Syndrome, Pulmonary Hypertension, and Heart Failure with Preserved Ejection Fraction. Am J Respir Cell Mol Biol. 2017 Apr;56(4):497-505.
Mora AL, Rojas M. Aging and lung injury repair: a role for bone marrow derived mesenchymal stem cells. J Cell Biochem. 2008 Oct 15; 105(3):641-7. PMID: 18759327.
Selman M, Rojas M, Mora AL, Pardo A. (2010) Aging and interstitial lung diseases: unraveling an old forgotten player in the pathogenesis of lung fibrosis. Semin Respir Crit Care Med. 31(5):607-17. (PMID 20941661)
Kapetanaki MG, Mora AL, and Rojas M. Influence of age on wound healing and fibrosis. J. Pathol. 2013. 229(2):310-22. PMID 231224998.
Rojas M, and Mora AL. Adult stem cells for chronic lung disease. 2013. Respirology, 18(7):1041-6. PMID 23648014.
Rojas M, Mora AL, Kapetanaki M, Weathington N, Gladwin M, Eickelberg O. Aging and Lung Disease. Clinical Impact and Cellular and Molecular Pathways. Ann Am Thorac Soc. 2015 Dec;12(12):S222-7.
Mora AL, Bueno M, Rojas M. Mitochondria in the spotlight of aging and idiopathic pulmonary fibrosis. J Clin Invest. 2017 Feb 1;127(2):405-414.