Faculty

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Description of Research Expertise

Dr. Krymskaya conducts basic and translational research focusing on the role of highly integrated signaling network merging on the PI3K-TSC2-mTOR in rare and common lung diseases. The work for which she receives the most recognition is discovery of the TSC2 function as a negative regulator of the mTOR. Her laboratory of Rare Lung Diseases was the first to establish human LAM cell cultures to perform preclinical testing and to demonstrate efficacy of rapamycin for inhibition of mTOR and abrogating LAM cell growth. This key evidence paved the way for two successful clinical trials and to FDA approval in 2015 of rapamycin analogs for treatment of LAM and TS-LAM. The discovery that TSC2 deregulates Rho GTPase and LAM cell survival through mTORC2 signaling and development of novel mouse model of LAM, led to preclinical study of novel combinational therapy for LAM, and phase 2 SOS clinical trial (clinicaltrials.gov, NCT02061397) to determine the safety of combined treatment of simvastatin and sirolimus or everolimus in patients with sporadic LAM and TS-LAM, on which Dr. Krymskaya was the Principal Investigator. Investigation into immunity in LAM, led to identification of PD-L1 upregulation in LAM lungs, developing a novel immunocompetent mouse model of LAM, and performance of preclinical study of anti-PD1 antibody to improve animal survival as a proof-of-principal for treatment of LAM. The recent study of LAM lung cell composition and novel LAM-relevant genetic animal model lay the groundwork for developing a novel mechanistic understanding of LAM pathobiology involving mTORC1-WNT signaling crosstalk and provide essential steps towards expending the repertoire of effective therapies for this devastating disease.

Description of Clinical Expertise

Principal Investigator of the SOS (Safety Study of Simvastatin in Patients with Sporadic Pulmonary Lymphangioleiomyomatosis (LAM) and LAM Associated with Tuberous Sclerosis Complex) clinical trial (ClinicalTrials.gov Identifier: NCT02061397)

Description of Other Expertise

Marketing management, concert piano

Selected Publications

Obraztsova K, Basil MC, Rue R, Sivakumar A, Lin SM, Mukhitov AR, Gritsiuta AI, Evans JF, Kopp M, Katzen J, Robichaud A, Atochina-Vasserman EN, Li S, Carl J, Babu A, Morley MP, Cantu E, Beers MF, Frank DB, Morrisey EE, Krymskaya VP: mTORC1 activation in lung mesenchyme drives sex- and age-dependent pulmonary structure and function decline. Nature Communications 11(1): 5640, Nov 2020 Notes: https://doi.org/10.1038/s41467-020-18979-4.

Evans JF, Obraztsova K, Lin SM, Krymskaya VP : CrossTORC and Wntegration in disease: Focus on Lymphangioleiomyomatosis. International Journal of Molecular Sciences 22(5): 2233-2248, February 2021 Notes: doi.org/10.3390/ijms22052233.

Krymskaya VP, Courtwright AM, Fleck V, Dorgan D, Kotloff R, McCormack FX, Kreider M: A phase II clinical trial of the Safety Of Simvastatin (SOS) in patients with pulmonary lymphangioleiomyomatosis and with tuberous sclerosis complex. Respiratory Medicine 163: 105898, Mar 2020 Notes: doi: 10.1016/j.rmed.2020.105898.

Evans JF, Rue RW, Mukhitov AR, Obraztsova K, Smith CJ, Krymskaya VP : Inhibition of growth of TSC2-null cells by a PI3K/mTOR inhibitor but not by a selective MNK1/2 inhibitor Biomolecules: Molecular Pathology, Molecular Mechanisms of Lung Diseases 10(1): 28, Dec 2019 Notes: doi: 10.3390/biom10010028.

Kovalenko A, Sanin A, Kosmas K, Zhang L, Wang J, Akl EW, Giannikou K, Probst CK, Hougard TR, Rue RW, Krymskaya VP, Asara JM, Lam HC, Kwiatkowski DJ, Henske EP, Filippakis H: Therapeutic targeting of DGKA-mediated macropinocytosis leads to phospholipid reprogramming in Tuberous Sclerosis Complex. Cancer Research 81(8): 2086-2100, Apr 2021 Notes: DOI: 10.1158/0008-5472.CAN-20-2218.

Li H, Oh HB, Viollet B, Schmidt LS, Linehan WM, Krymskaya VP, Hong SB: Requirement of FLCN tumor suppressor gene for mTORC1-mediated inhibition of TFE3 transcriptional activity. bioRxiv Jul 2020 Notes: doi: https://doi.org/10.1101/2020.07.08.193169.

Han F, Dellacecca ER, Barse LW, Cosgrove C, Henning SW, Ankney CM, Jaishankar D, Yemelyanov A, Krymskaya VP, Dilling DF, Le Poole IC: Adoptive T cell transfer to treat lymphangioleiomyomatosis. American Journal of Respiratory Cell and Molecular Biology 62(6): 793-804, Jun 2020 Notes: doi: 10.1165/rcmb.2019-0117OC.

Krymskaya VP, McCormack FX: Lymphangioleiomyomatosis: a monogenic model of malignancy. Annual Review of Medicine 68: 69-83, Jan 2017 Notes: NIHMSID: 889033.

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Last updated: 09/06/2021
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