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
tel.: (215) 573-9861
fax: (215) 746-1224
email: krymskay@mail.med.upenn.edu
Education: 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
Postdoctoral Fellowships: 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
Research in Krymskaya lab is focused on signal transduction pathways underlying rare and common lung diseases, including pulmonary lymphangioleiomyomatosis (LAM), Birt-Hogg-Dube (BHD), pulmonary arterial hypertension in collaboration with Dr. Elena Goncharova, chronic obstructive pulmonary disease (COPD), and asthma in collaboration with Dr. Reynold Panettieri, Jr. and finding novel therapeutic approaches for their treatment.
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..
Selected publications
- Medvetz DA, Khabibullin D, Hariharan V, Ongusaha PP, Goncharova EA, Schlechter T, Darling TN, Hofmann I, Krymskaya VP, Liao JK, Huang H, Henske EP. Folliculin, the Product of the Birt-Hogg-Dube Tumor Suppressor Gene, Interacts with the Adherens Junction Protein p0071 to Regulate Cell-Cell Adhesion. PLoS One. 2012;7(11):e47842. Epub 2012 Nov 6.
- Goncharova EA, Goncharov DA, Fehrenbach M, Khavin I, Ducka B, Hino O, Colby TV, Merrilees MJ, Haczku A, Albelda SM, Krymskaya VP. Prevention of Alveolar Destruction and Airspace Enlargement in a Mouse Model of Pulmonary Lymphangioleiomyomatosis (LAM). Sci Transl Med. 2012 Oct 3;4(154):154ra134.
- Moir LM, Black JL, Krymskaya VP. TSC2 modulates cell adhesion and migration via integrin-a1B1. Am J Physiol Lung Cell Mol Physiol. 2012 Oct; 303(8):L703-10. Epub 2012 Aug 24.
- Koziol-White CJ, Goncharova EA, Cao G, Johnson M, Krymskaya VP, Panettieri RA Jr. DHEA-S inhibits human neutrophil and human airway smooth muscle migration. Biochim Biophys Acta. 2012 Jul 3. [Epub ahead of print]
- Krymskaya VP. Treatment Option(s) for Pulmonary Lymphangioleiomyomatosis: Progress and Current Challenges. Am J Respir Cell Mol Biol 2012; 46(5):563-565.
- Goncharova EA, Goncharov DA, Zhao H, Penn RB, Krymskaya VP, Panettieri RA Jr. Beta2-adrenergic receptor agonists modulate human airway smooth muscle cell migration via vasodilator-stimulated phosphoprotein. Am J Respir Cell Mol Biol. 2012 Jan; 46(1):48-54.
- Damera G, Druey KM, Cooper PR, Krymskaya VP, Soberman RJ, Amrani Y, Hoshi T, Brightling CE, Panettieri RA Jr. An RGS4-mediated phenotypic switch of bronchial smooth muscle cells promotes fixed airway obstruction in asthma. PLoS One. 2012; 7(1):e28504. Epub 2012 Jan 12.
- Moir LM, Ng HY, Poniris MH, Santa T, Burgess JK, Oliver BG, Krymskaya VP, Black JL. Doxycycline inhibits matrix metalloproteinase-2 secretion from TSC2-null mouse embryonic fibroblasts and lymphangioleiomyomatosis cells. Br J Pharmacol. 2011 Sep;164(1):83-92
- Goncharova EA, Goncharov DA, Zhao H, Penn RB, Krymskaya VP, Panettieri Jr RA. {beta}2AR Agonists Modulate Human Airway Smooth Muscle Cell Migration Via VASP. Am J Respir Cell Mol Biol. 2011 Jul 28
- Goncharova EA, Goncharov DA, Li H, Pimtong W, Lu S, Khavin I, Krymskaya VP. mTORC2 is required for proliferation and survival of TSC2-null cells. Mol Cell Biol. 2011 Jun;31(12):2484-98.
