Our laboratory focuses on the role of post-translational modifications of proteins, especially polyubiquitnation of the key mediators of vascular pathologies in diseases such as cancer and renal failure. While these diseases are discrete, several fundamental biological processes remain similar. Through a highly collaborative network, our laboratory harnesses the power of various cellular and molecular biological tools, relevant animal models (zebrafish and mice), computational methods and machine-learning techniques and strives to validate these findings and hypotheses in humanized models or human samples from large data bases, which highlights the translational nature of our approach.
A. Vascular diseases in kidney failure: Close to 20 million Americans or 10% of US population suffer from the chronic kidney disease (CKD). Among plethora of cardiovascular manifestations, CKD patients are particularly at high risk for both venous and arterial thrombosis, especially after vascular injury (endovascular injury such as angioplasty or stents; and surgical injury such as arteriovenous fistula creation) in CKD patients. This area of CKD management warrants urgent investigation due to lack of risk predictors and CKD-specific therapeutic targets.
Renal failure results in the retention of several chemical compounds, which unleash cellular toxicity, and hence called uremic solutes/toxins. While investigating the molecular pathogenesis of uremic toxicity, our laboratory was the first to demonstrate the prothrombotic propensity of indolic uremic solutes, which inhibits the ubiquitination of tissue factor, a bona fide member of the extrinsic coagulation pathway. Further investigation revealed Aryl Hydrocarbon Receptor (AHR) pathway as a critical mediator of tissue factor ubiquitination and thrombosis. Leveraging the ligand and the mediator, our lab aims to gain a deeper understanding into the mechanism of this unique uremic thrombosis axis (uremic solutes- AHR- TF- thrombosis) and to develop biomarkers and novel compounds to improve the management of the CKD patients with thrombosis after interventions in various vascular beds including coronary artery and arteriovenous fistula, etc.
Thrombosis being a dynamic and the multicomponent process, our laboratory has taken a holistic approach, under the co-directorship of Drs. Chitalia and Ravid, the Department of Medicine of BUSM and established a Thrombosis and Hemostasis ARC, which is a multidisciplinary platform of cell and molecular biologists, clinicians (cardiologists, vascular medicine, nephrologists and hematologists), computational biologists, biomedical engineers and statisticians and mathematicians to investigate various facets of thrombosis. http://www.bumc.bu.edu/evanscenteribr/the-arcs/the-arcs/
B. Angiogenesis: Angiogenesis, a process of generation of novel blood vessel is fundamental during the development and in various diseases such as cancer. Wnt signaling, a highly conserved oncogenic pathway is critical in angiogenesis. Beta catenin is the prime mediator of Wnt activation. Focusing on the ubiquitination and proteasomal degradation of beta catenin, our previous work had described Jade-1, as an E3 ligases of wild-type beta catenin. Our recent efforts have specifically focused on c-Cbl as an E3 ligase for the mutant beta catenin and for the transcriptionally active beta catenin in the nucleus. These two species of beta catenin, once considered resistant to degradation are effectively downregulated by c-Cbl. Thus, c-Cbl is a unique E3 ligase of tumorigenic beta catenin, which is involved in several cancers including colorectal cancer pathogenesis. Leveraging the cancer animal models and human cancer samples including machine learning based quantitative histology! techniques, our group investigates the colorectal cancer pathogenesis to gain deeper understanding of the role of E3 ligases of beta catenin E3 ligases in various cancers.