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Research at COVP

Vascular Diseases in Cancer

Cancer progresses through several steps characterized by a conversion of normal tissue states to anaplasia and neoplasia. While the tumor continues to grow in a conducive environment, it draws leash of blood vessels along with it. Angiogenesis, a process of generation of novel blood vessels 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 has described Jade-1, as an ubiquitin ligase of wild-type beta catenin. Our recent efforts have specifically focused on c-Cbl as an E3 ligase for the mutant beta-catenin and the transcriptionally active beta-catenin in the nucleus. These two species of beta-catenin, once considered resistant to degradation, are the key mediators of tumorigenesis and 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 a deeper understanding of the role of E3 ligases of beta-catenin E3 ligases in various cancers.

Vascular Diseases in Kidney Failure

Close to 20 million Americans, or 10% of the US population, suffer from chronic kidney disease (CKD). Among a 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). This area of CKD management warrants urgent investigation due to the lack of risk predictors and CKD-specific therapeutic targets.

Renal failure results in the retention of several chemical compounds, which unleash cellular toxicity and are 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 inhibit 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 of the mechanism of this unique uremic thrombosis axis (uremic solutes- AHR- TF- thrombosis). In addition, we yearn to develop biomarkers and novel compounds to improve the management of CKD patients with thrombosis after interventions in various vascular beds including coronary artery and arteriovenous fistula, etc.

Thrombosis, being a dynamic and multicomponent process, our laboratory has taken a holistic approach, under the co-directorship of Drs. Chitalia and Ravid, the Department of Medicine of BUSM, 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.

Biomedical Engineering Application to Kidney Problems

The era of precision medicine warrants a multi-pronged approach to develop better biomarkers or therapeutic targets. Leveraging a rich interdisciplinary network of biomedical engineers, computation biologists, synthetic chemists, polymer chemists, and health economists. Kidney problems and their potential solution lend themselves to the biomedical engineering approach. Two major areas remain the focus of our effort – bioimaging to evaluate the extent of kidney damage and vascular disease in CKD and bioengineering approaches to develop targeted dialyzer membrane to remove cardiotoxic uremic solutes. We have developed an elastic light scattering spectrometry (ESS) to detect renal fibrosis from fresh kidney tissue. Using the computation biology team along with machine learning and artificial intelligence to develop multi-scale predictive models of chronic kidney disease or its complications such as thrombosis. The current hemodialysis technique fails to remove pathogenic toxins that are retained in these patients. These uremic toxins contribute to fatal cardiovascular events such as stroke and heart attacks, as well as anemia, rapid aging, alterations in drug metabolism, bone weakness, and infertility. Spearheaded by Dr. Vipul Chitalia (BU and Global Co-creation Labs -GCL, MIT), John Porco, David Coker and Lauren Brown (Chemistry, BU), and Arturo Vega (BME, BU) will develop modified dialysis membranes to selectively trap pathogenic uremic toxins. In the spirit of interdisciplinary research, this project will be benefitted from the collaboration between BU and GCL, IMES, and MIT represented by Dr. Chitalia and Mr. Spencer Moss (MBA, GCL, MIT Sloan) who will head the business development of this project. The development of a ‘smarter dialyzer’ heralds an era beyond the incremental changes in the hemodialysis technique observed since its inception.

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