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.
- Member, Whitaker Cardiovascular Institute, Boston University
- Member, Evans Center for Interdisciplinary Biomedical Research, Boston University
- Graduate Faculty (Primary Mentor of Grad Students), Boston University School of Medicine, Graduate Medical Sciences
- BU Profile
- Chitalia Lab
- Press Release: Key Protein
- ThromboARC (Dept of Medicine)
- Collaborator: Edelman Lab
- Ravid lab
- Collaborator: Rahimi lab
- Collaborator: Sherr lab
- Collaborator: Kolachalama lab
- Hariri Institute for Computing and Computational Science & Engineering
- Boston Medical Center Provider Profile
- Seth G.S. Medical College, MD
- Lokmanya Tilak Medical College and Hospital, MBBS
- Seth G.S. Medical College, DM
- Published on 9/2/2020
Ravid JD, Chitalia VC. Molecular Mechanisms Underlying the Cardiovascular Toxicity of Specific Uremic Solutes. Cells. 2020 Sep 02; 9(9). PMID: 32887404.
- Published on 8/20/2020
Matsuura S, Thompson CR, Belghasem ME, Bekendam RH, Piasecki A, Leiva O, Ray A, Italiano J, Yang M, Merill-Skoloff G, Chitalia VC, Flaumenhaft R, Ravid K. Platelet Dysfunction and Thrombosis in JAK2V617F-Mutated Primary Myelofibrotic Mice. Arterioscler Thromb Vasc Biol. 2020 Aug 20; ATVBAHA120314760. PMID: 32814440.
- Published on 6/23/2020
Amraie R, Napoleon MA, Yin W, Berrigan J, Suder E, Zhao G, Olejnik J, Gummuluru S, Muhlberger E, Chitalia V, Rahimi N. CD209L/L-SIGN and CD209/DC-SIGN act as receptors for SARS-CoV-2 and are differentially expressed in lung and kidney epithelial and endothelial cells. bioRxiv. 2020 Jun 23. PMID: 32607506.
- Published on 2/26/2020
Richards S, Walker J, Nakanishi M, Belghasem M, Lyle C, Arinze N, Napoleon MA, Ravid JD, Crossland N, Zhao Q, Rosenberg D, Rahimi N, Chitalia VC. Haploinsufficiency of Casitas B-Lineage Lymphoma Augments the Progression of Colon Cancer in the Background of Adenomatous Polyposis Coli Inactivation. Am J Pathol. 2020 03; 190(3):602-613. PMID: 32113662.
- Published on 2/1/2020
Addo-Tabiri NO, Chudasama R, Vasudeva R, Leiva O, Garcia B, Ravid JD, Bunze T, Rosen L, Belghasem M, Francis J, Brophy M, Johnson B, Ferguson R, Weinberg J, Chitalia VC. Black Patients Experience Highest Rates of Cancer-associated Venous Thromboembolism. Am J Clin Oncol. 2020 02; 43(2):94-100. PMID: 31809329.
- Published on 12/27/2019
Lyle C, Richards S, Yasuda K, Napoleon MA, Walker J, Arinze N, Belghasem M, Vellard I, Yin W, Ravid JD, Zavaro E, Amraei R, Francis J, Phatak U, Rifkin IR, Rahimi N, Chitalia VC. c-Cbl targets PD-1 in immune cells for proteasomal degradation and modulates colorectal tumor growth. Sci Rep. 2019 12 27; 9(1):20257. PMID: 31882749.
- Published on 12/26/2019
Belghasem M, Roth D, Richards S, Napolene MA, Walker J, Yin W, Arinze N, Lyle C, Spencer C, Francis JM, Thompson C, Andry C, Whelan SA, Lee N, Ravid K, Chitalia VC. Metabolites in a mouse cancer model enhance venous thrombogenicity through the aryl hydrocarbon receptor-tissue factor axis. Blood. 2019 12 26; 134(26):2399-2413. PMID: 31877217.
- Published on 10/30/2019
Walker JA, Richards S, Belghasem ME, Arinze N, Yoo SB, Tashjian JY, Whelan SA, Lee N, Kolachalama VB, Francis J, Ravid K, Sherr D, Chitalia VC. Temporal and tissue-specific activation of aryl hydrocarbon receptor in discrete mouse models of kidney disease. Kidney Int. 2020 03; 97(3):538-550. PMID: 31932072.
- Published on 10/21/2019
Leiva O, Ng SK, Matsuura S, Chitalia V, Lucero H, Findlay A, Turner C, Jarolimek W, Ravid K. Novel lysyl oxidase inhibitors attenuate hallmarks of primary myelofibrosis in mice. Int J Hematol. 2019 Dec; 110(6):699-708. PMID: 31637674.
- Published on 6/7/2019
Leiva O, Bekendam RH, Garcia BD, Thompson C, Cantor A, Chitalia V, Ravid K. Emerging Factors Implicated in Fibrotic Organ-Associated Thrombosis: The Case of Two Organs. TH Open. 2019 Apr; 3(2):e165-e170. PMID: 31259299.
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