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.
- Graduate Faculty (Primary Mentor of Grad Students), Boston University School of Medicine, Division of Graduate Medical Sciences
- Active Staff Hospital Privileges, Medicine, Boston Medical Center
- Seth G.S. Medical College, MD
- Lokmanya Tilak Medical College and Hospital, MBBS
- Seth G.S. Medical College, DM
- Published on 7/17/2018
Kumaradevan S, Lee SY, Richards S, Lyle C, Zhao Q, Tapan U, Jiangliu Y, Ghumman S, Walker J, Belghasem M, Arinze N, Kuhnen A, Weinberg J, Francis J, Hartshorn K, Kolachalama VB, Cifuentes D, Rahimi N, Chitalia VC. c-Cbl Expression Correlates with Human Colorectal Cancer Survival and Its Wnt/ß-Catenin Suppressor Function Is Regulated by Tyr371 Phosphorylation. Am J Pathol. 2018 Aug; 188(8):1921-1933. PMID: 30029779.
- Published on 4/1/2018
Reddy YNV, Nunes D, Chitalia V, Gordon CE, Francis JM. Hepatitis C virus infection in kidney transplantation-changing paradigms with novel agents. Hemodial Int. 2018 Apr; 22 Suppl 1:S53-S60. PMID: 29694721.
- Published on 1/17/2018
Kolachalama VB, Shashar M, Alousi F, Shivanna S, Rijal K, Belghasem ME, Walker J, Matsuura S, Chang GH, Gibson CM, Dember LM, Francis JM, Ravid K, Chitalia VC. Uremic Solute-Aryl Hydrocarbon Receptor-Tissue Factor Axis Associates with Thrombosis after Vascular Injury in Humans. J Am Soc Nephrol. 2018 Mar; 29(3):1063-1072. PMID: 29343519.
- Published on 1/11/2018
Kolachalama VB, Singh P, Lin CQ, Mun D, Belghasem ME, Henderson JM, Francis JM, Salant DJ, Chitalia VC. Association of Pathological Fibrosis With Renal Survival Using Deep Neural Networks. Kidney Int Rep. 2018 Mar; 3(2):464-475. PMID: 29725651.
- Published on 1/1/2018
Vijaya B. Kolachalama, Moshe Shashar, Faisal Alousi, Sowmya Shivanna, Keshab Rijal, Mostafa Belghasem, Joshua Walker, Shinobu Matsuura, C Michael Gibson, Laura M. Dember, Jean M. Francis, Katya Ravid, Vipul C. Chitalia. . Journal of American Association of Nephrology (in press) . Uremic solute-Aryl Hydrocarbon Receptor-Tissue Factor Axis Associates with Post-Vascular Injury Thrombosis in Humans . 2018; (March).
- Published on 1/1/2018
Vijaya B. Kolachalama, Priyamvada Singh, Christopher Q. Lin, Dan Mun, Mostafa E. Belghasem, Joel M. Henderson, Jean M. Francis, David J. Salant and Vipul C. Chitalia. . Association of Pathological Fibrosis With Renal Survival Using Deep Neural Networks. Kidney International Reports 2018 (in press). 2018.
- Published on 11/22/2017
Shashar M, Belghasem ME, Matsuura S, Walker J, Richards S, Alousi F, Rijal K, Kolachalama VB, Balcells M, Odagi M, Nagasawa K, Henderson JM, Gautam A, Rushmore R, Francis J, Kirchhofer D, Kolandaivelu K, Sherr DH, Edelman ER, Ravid K, Chitalia VC. Targeting STUB1-tissue factor axis normalizes hyperthrombotic uremic phenotype without increasing bleeding risk. Sci Transl Med. 2017 Nov 22; 9(417). PMID: 29167396.
- Published on 9/18/2017
Woolf N, Pearson BE, Bondzie PA, Meyer RD, Lavaei M, Belkina AC, Chitalia V, Rahimi N. Targeting tumor multicellular aggregation through IGPR-1 inhibits colon cancer growth and improves chemotherapy. Oncogenesis. 2017 Sep 18; 6(9):e378. PMID: 28920928.
- Published on 8/19/2017
Al-Rabadi L, Quillen K, Shashar M, Al Marji C, Jaberi A, Chitalia V, Henderson J, Salant D, Beck LH. Concurrent Presentation of Thrombotic Thrombocytopenic Purpura and Membranous Nephropathy. Kidney Int Rep. 2018 Mar; 3(2):476-481. PMID: 29725652.
- Published on 7/31/2017
Zhang A, Rijal K, Ng SK, Ravid K, Chitalia V. A mass spectrometric method for quantification of tryptophan-derived uremic solutes in human serum. J Biol Methods. 2017; 4(3). PMID: 29707597.
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