Kishore K Wary

Current Projects

1. Lipid Phosphate Phosphatase-3 (LPP3 aka PPAP2b) in the Regulation of Vascular Inflammation and Remodeling

Genome-wide association studies (GWAS) of coronary heart disease (CHD) identified LPP3 (also known as PPAP2b) loci as one of the most frequently occurring variations associated with CHD. Interestingly, we discovered LPP3/PPAP2b in a functional assay of angiogenesis (EMBO J, 2013). Traditionally LPP3 is known to release phosphate group from Sphingosine-1-Phosphate (S1P), Ceramide-1-Phoshate (C1P) and Lysophosphatidic acid phosphate (LPA). However, how does LPP3 regulate vascular inflammation and remodeling is not known. Lpp3-deficient embryos die in utero due to lack of functional blood vessels. To address the role of Lpp3 in postnatal vascular bed, we have developed unique mice to elucidate the role of LPP3 in endothelial cells.

2. Role of Krüppel Like Factor-4 (KLF4) and NANOG in Adult Organ Regeneration

We have demonstrated that Wnt3a induced the expression of KLF4 and that event regulated VE-cadherin expression at the level of the adherens junctions (Circ Res, 2010). Moreover, Wnt3a induced expression of NANOG, which then bound to and activated the FLK1/VEGFR2 promoter to regulate angiogenesis (Blood, 2011). These findings suggest that a subset of endothelial cells have the ability to de-differentiate into immature endothelial cells. Expanding upon these findings, now we are testing small molecules and employing genetic methods to induce dedifferentiation of endothelial cells, and these efforts are geared towards either increasing and or re-establishing blood flow to the ischemic tissues. In addition, we are also using stem cells and iPS cells for this project, and are also using cell based reporter assays and transgenic mice for these studies. We will address the mechanisms of therapeutic benefit.

3. Drug Screening and Experimental Therapeutics

In this project, we are using small molecules and genetic methods to convert venous endothelial cells into arterial endothelial cells, a process called “de-differentiation” or “limited reprogramming” within its own lineage . Thereafter, we hope to evaluate the function and epigenetic status of reprogrammed cells by monitoring methylation of imprinted and stemness genes, and address the question of “epigenetic memory”, i.e., if these cells remember where they came from. To address above described projects, we use cultured primary cells, embryonic stem (ES) cells, and induced pluripotent stem (iPS) cells, and small laboratory animals.

Chatterjee I, Baruah J, Lurie EE, Wary KK. Endothelial lipid phosphate phosphatase-3 deficiency that disrupts the endothelial barrier function is a modifier of cardiovascular development. Cardiovasc Res. 111(1):105-18, 2016.

Gong H, Rehman J, Tang H, Wary K, Mittal M, Chaturvedi P, Zhao YY, Komarova YA, Vogel SM, Malik AB. HIF2α signaling inhibits adherens junctional disruption in acute lung injury. J Clin Invest. 125:652-64, 2015.

Wu L, Wary KK, Revskoy S, Gao X, Tsang K, Komarova YA, Rehman J, Malik AB. Histone Demethylases KDM4A and KDM4C Regulate Differentiation of Embryonic Stem Cells to Endothelial Cells. Stem Cell Reports. 5:10-21, 2015.

Toya SP, Wary KK, Mittal M, Li F, Toth PT, Park C, Rehman J, Malik AB. Intergrin alpha6beta1 Expressed in ESCs Instructs the Differentiation to Endothelial Cells. Stem Cells. 33:1719-29, 2015.

Kohler EE, Cowan CE, Chatterjee I, Malik AB, Wary KK. NANOG induction of Fetal liver kinase-1 (FLK1) transcription regulates endothelial cell proliferation and angiogenesis. Blood. 117:1761-1769, 2011.

Cowan CE, Kohler EE, Dugan TA, Mirza MK, Malik AB, Wary KK. Krüppel-like factor-4 transcriptionally regulates VE-cadherin expression and endothelial barrier function. Circ Res. 107:959-966, 2010.

Humtsoe JO, Liu M, Malik AB, Wary KK. Lipid phosphate phosphatase-3 stabilization of β-catenin induces endothelial cell migration and formation of branching point structures. Mol Cell Biol. 30:1593-1606, 2010.