The Krymskaya lab 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 we receive the most recognition is discovery of the TSC2 function as a negative regulator of the mTOR. My lab 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.

Our basic and translational studies about a key role of Rho GTPase in LAM cell survival demonstrated in a novel mouse model of LAM (currently used in many labs worldwide), led to phase 2 SOS clinical trial (clinicaltrials.gov, NCT02061397). 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. Our current 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.