SB, Massachusetts Institute of Technology 1984
MD, PhD John Hopkins University 1992
Tinman Article in MUSC Progress Notes
The Lee laboratory focus on early heart development, particularly as it pertains to mechanisms causing congenital heart disease in humans.
We currently study the genetic pathways leading to and emanating from the early cardiac transcription factor, Nkx2-5, which has long been associated with congenital anomalies. Alteration of Nkx2-5 expression levels has a profound effect on development of the Second Heart Field (SHF), a distinct set of heart precursors which gives rise to both outflow tract (OFT) and right ventricle at the aortic pole of the embryonic heart. Disruption of Nkx2-5 expression in mouse models results in a spectrum of defects from severe hypoplasia of OFT and right ventricle to milder OFT rotation or alignment defects such as double outlet right ventricle (DORV). Missense mutations of Nkx2-5 in human kindreds are similarly associated with OFT defects like DORV and Tetralogy of Fallot. This represents a significant clinical association: of the congenital heart anomalies that occur in nearly one percent of all human live births, nearly one-third involve the OFT and associated aorta and pulmonary artery.
Our efforts are directed towards two main pathways to discovery:
- Identification of the direct downstream gene targets of the Nkx2-5 transcription factor in cells of the second heart field.
- Delineation of the transcriptional regulation of Nkx2-5 in second heart field.
The Lee laboratory has also begun a pilot effort to understand the linkage between ectopic expression of Nkx2-5 in human placenta, and pre-eclampsia, or hypertension and proteinuria in pregnancy. Pre-eclampsia (PE) occurs in 2-7% of all pregnancies, and is a leading cause of maternal morbidity and premature birth. We have recently found unusually high levels of Nkx2.5 expression in placental trophoblast cells in a subset of women with early onset and severe pre-eclampsis (EOSPE) associated with high levels of an emerging marker of pre-eclampsia, the anti-angiogenic factor sFlt-1. We hypothesize that this linkage is due to the activation of expression of an Nkx2-5 target gene, khdrbs1/Sam68, which may influence production of sFlt-1 transcripts through regulation of alternative mRNA splicing of the parent VEGFR1 RNA.
Interestingly, the statistical linkage between Nkx2-5 and sFlt-1 levels show racial differences, which may lead to novel insights into both distinct causes of PE between individuals, and the factors related to differential disease incidence and severity between racial groups.
Lee lab PE research efforts are directed toward human and animal model efforts:
Experimental Systems in Use
- Expanded human tissue expression profiling to further explore racial and etiologic associations between elevated Nkx2-5 and target gene expression and disease.
- Use of mouse models testing the effect of abnormal Nkx2-5 expression in the placenta on development and maternal morbidity during pregnancy.
- Rivers ER, Horton AJ, Hawk AF, Favre EG, Senf KM, Nietert PJ, Chang EY, Foley AC, Robinson CJ, Lee K.H. Placental Nkx2-5 and target gene expression in early-onset and severe preeclampsia. Hypertens Pregnancy. 2014 Jul 2:1-15. PMID: 24987805
- Clark, C. D., Zhang, B., Lee, B., Evans, S. I., Lassar, A. B., and Lee, K. H. (2012) Evolutionary Conservation of Nkx2.5 Autoregulation in the Second Heart Field. Dev. Biol. 374 (1):198-209. PMCID: PMC3549048
- Brody, M. J., Mysliwiec, M. R., Kim, T. G., Carlson, C. D., Cho, E. Lee, K. H. and Lee, Y. S. (2013) Lrrc10 is a novel cardiac-specific target gene of Nkx2-5 and GATA4. J. Molec. Cell Cardiol. S0022-2828 (13): 198-203. PMID: 23751912.
- Barth, J.L., Clark, C.D., Fresco, V.M., Knoll, E.P., Lee, B., Argraves, W.S., and Lee, K.H. (2010). Jarid2 is among a set of genes differentially regulated by Nkx2.5 during outflow tract morphogenesis. Dev Dyn 239, 2024-2033.
- Ikeda, S., He, A., Kong, S.W., Lu, J., Bejar, R., Bodyank, N., Lee, K.H., Ma, Q., Kang, P., Golub, T., and Pu,
W.T. (2009) microRNA-1 attenuates cardiomyocyte hypertrophy by negatively regulating calmodulin and
Mef2a. Mol. Cell. Biol. 29(8):2193-204.
- Rivera-Feliciano, J., Lee, K.H., Kong, S.W., Ma, Q., Springer, Z., Izumo, S., Tabin, C.J. and Pu, W.T. (2006) Development of heart valves requires Gata4 expression in endocardium derived cells. Development 133(18): 3607-18.
- Lee, K. H., Evans, S., Ruan, T. Y., and Lassar, A. B. (2004). Smad-mediated modulation of YY1 activity regulates the BMP response and cardiac-specific expression of a GATA-4,-5,-6 dependent chick Nkx-2.5 enhancer. Development 131: 4709-4723.