Vera Krymskaya, Ph.D., M.B.A.
Associate Professor of Medicine
University of Pennsylvania Medical Center
Pulmonary, Allergy, & Critical Care Division
Translational Research Laboratories (TRL)
125 South 31st Street, TRL Suite 1200
Philadelphia, PA 19104-3413
College of Physicians of Philadelphia
19 South 22nd Street
Philadelphia, PA 19103
Ph.D., Department of Biophysics, Moscow State University, Moscow, USSR
M.B.A., Marketing Management, Plekhanov Institute of Economics, Moscow, USSR
B.A., Piano, Krushelnizka Music College, Ternopil, Ukraine
Laboratory of Radiation Biochemistry and Cellular Regulation, Institute of Cell Biophysics Russian Academy of Sciences, Moscow, USSR
Laboratory of Molecular Endocrinology, Institute of Experimental Cardiology, Cardiology Research Center, Russian Academy of Medical Sciences, Moscow, USSR
Pulmonary and Critical Care Division, Department of Medicine, University of Pennsylvania, Philadelphia, PA
Laboratory of Rare Lung Diseases at the Airways Biology Initiative
The Airways Biology Initiative (ABI), at the Pulmonary, Allergy & Critical Care Division, Perelman School of Medicine University of Pennsylvania conducts basic research in gaining a detailed molecular understanding of a highly integrated signaling networks in rare and common lung diseases, including sporadic pulmonarylymphangioleiomyomatosis (LAM), Tuberous Sclerosis (TS)-associated LAM, Birt-Hogg-Dube (BHD),pulmonary arterial hypertension (PAH), and chronic obstructive pulmonary disease (COPD). The ability to properly perceive and integrate signals from growth factors, cytokines, proinflammatory mediators, energy, nutrients, and environmental stresses at both the cellular and organismal levels is essential for the prevention of pulmonary diseases. To elucidate the detailed mechanisms of pathways underlying these processes and to find novel therapeutic targets, the laboratory uses a multidisciplinary approach including protein and lipid biochemistry, cell and molecular biology, genetics, and animal models of disease. Our laboratory is renowned for establishing state-of-the-art clinical and research programs that translate discoveries into new therapeutics for patients with orphan diseases such as lymphangioleiomyomatosis and Birt-Hogg-Dube syndrome. Further, as part of the ABI Laboratory of Rare Lung Diseases provides unique opportunities for undergraduate, graduate and postdoctoral research, clinical education and training using state-of-the-art facilities.
Current basic research projects open to fellow participation:
Bench (basic & translational) projects:
TSC Signaling and Pulmonary LAM
Pulmonary LAM is a rare lung disease affecting predominantly women of childbearing age that is associated with mutational inactivation of the Tuberous Sclerosis Complex (TSC1 or TSC2) tumor suppressor genes. LAM that can be sporadic or associated with tuberous sclerosis (TS), is manifested by neoplastic growth of LAM cells, lung cyst formation, obstruction of lymphatics, and spontaneous pneumothoraces. Our group participated in the discovery that the TSC genes function as negative regulators of the mammalian target of rapamycin complex 1 (mTORC1), an observation that has led to the promising use of rapamycin in clinical trials. However, despite this key finding, little is known about how TSC loss in LAM cells induces lung cyst formation and whether cystic lung destruction in LAM can be ameliorated. This project has two major goals: 1) to determine how growth of TSC2-null lesions in the lung induces cystic airspace enlargement; and 2) to perform proof-of-concept preclinical studies of therapeutic targeting of TSC2-dependent cell signaling to inhibit TSC2-deficient tumor growth and airspace enlargement in the TSC2-null mouse model of LAM. Our studies will elucidate the signal transduction pathways that inhibit lung cyst formation and will provide insights about potential novel molecular targets and potential combinational therapy to treat LAM.
Role of Folliculin in Lung Cell Survival: Relevance to BHD
Cystic airspace enlargement and spontaneous pneumothorax are major pathological manifestations of BHD, a rare lung disease linked to the mutational inactivation of tumor suppressor gene folliculin (FLCN). Currently, no therapy exists for the treatment of BHD patients to prevent cystic airspace enlargement and recurring pneumothoraces. The cellular signaling by FLCN, a 64-kDa ubiquitously expressed protein with high homology throughout species, however, is not well understood. Evidence suggests that FLCN acts within the nutrient and energy sensing signaling networks regulated by tuberous sclerosis complex 2 (TSC2) - mammalian target of rapamycin (mTOR) and 5’-AMP-activated protein kinase (AMPK), a master regulator of cellular energy metabolism, epithelial cell junctions assembly and polarity. Although FLCN loss has been linked to lung cyst formation in BHD the key question remains: how FLCN-induced deregulation of cellular signaling leads to the cystic airspace enlargement characteristic of BHD. Our goal is to establish a mechanistic link between loss of FLCN and cystic airspace enlargement; to further elucidate the signal transduction pathways that modulate lung epithelial cell metabolism and survival, and to provide insights about potential novel molecular targets and potential therapy to treat BHD syndrome..
- Atochina-Vasserman EN, Abramova E, James ML, Rue R, Liu AY, Ersumo NT, Guo CJ, Gow AJ, Krymskaya VP. Pharmacological targeting of VEGFR signaling with axitinib inhibits Tsc2-null lesion growth in the mouse model of lymphangioleiomyomatosis (LAM). Am J Physiol Lung Cell Mol Physiol. 2015 Oct 2:ajplung.00262.2015. [Epub ahead of print]
- Ng HY, Oliver BG, Burgess JK, Krymskaya VP, Black JL, Moir LM. Doxycycline reduces the migration of tuberous sclerosis complex-2 null cells - effects on RhoA-GTPase and focal adhesion kinase. J Cell Mol Med. 2015 Aug 18. [Epub ahead of print]
- Clements D, Dongre A, Krymskaya VP, Johnson SR. Wild Type Mesenchymal Cells Contribute to the Lung Pathology of Lymphangioleiomyomatosis. PloS One. 2015 May 15;10(5):e0126025. eCollection 2015.
- Atochina-Vasserman EN, Guo CJ, Abramova E, Golden TN, Sims M, James ML, Beers MF, Gow AJ, Krymskaya VP. Surfactant Dysfunction and Lung Inflammation in the Female Mouse Model of Lymphangioleiomyomatosis (LAM). Am J Respir Cell Mol Biol. 2014 Dec 4. [Epub ahead of print]
- Goncharova EA, James ML, Kudryashova TV, Goncharov DA, Krymskaya VP. Tumor Suppressors TSC1 and TSC2 Differentially Modulate Actin Cytoskeleton and Motility of Mouse Embryonic Fibroblasts. PLoS One. 2014 Oct 31;9(10):e111476. eCollection 2014.
- Goncharova EA, Goncharov DA, James ML, Atochina-Vasserman EN, Stepanova V, Hong S-B, Li H, Gonzales L, Baba M, Linehan WM, Gow AJ, Margulies S, Guttentag S, Schmidt LS, and Krymskaya VP. Folliculin Controls Lung Alveolar Enlargement and Epithelial Cell Survival through E-Cadherin, LKB1, and AMPK. Cell Report, April 2014 [Epub ahead of print]
- Goncharov DA, Kudryashova TV, Ziai H, Ihida-Stansbury K, Delisser H, Krymskaya VP, Tuder RM, Kawut SM, Goncharova EA. mTORC2 Coordinates Pulmonary Artery Smooth Muscle Cell Metabolism, Proliferation and Survival in Pulmonary Arterial Hypertension. Circulation. 2013 Nov 22. [Epub ahead of print]
- Atochina-Vasserman EN, Goncharov DA, Volgina AV, Milavec M, James ML, Krymskaya VP. Statins in Lymphangioleiomyomatosis. Simvastatin and Atorvastatin Induce Differential Effects on tuberous sclerosis complex 2-Null Cell Growth and Signaling. Am J Respir Cell Mol Biol. 2013 Aug 15.
- Parker WE, Orlova KA, Parker WH, Birnbaum JF, Krymskaya VP, Goncharov DA, Baybis M, Helfferich J, Okochi K, Strauss KA, Crino PB. Rapamycin Prevents Seizures After Depletion of STRADA in a Rare Neurodevelopmental Disorder. Sci Transl Med. 2013 Apr 24;5(182)
- Goncharova EA, Khavin IS, Goncharov DA, Krymskaya VP. Differential effects of formoterol on thrombin- and PDGF-induced proliferation of human pulmonary arterial vascular smooth muscle cells. Respir Res. 2012 Nov 27;13(1):109. [Epub ahead of print]