Dr. Navin Varadarajan
Assistant Professor

Dept. of Chemical and Biomolecular Engineering
S222 Engineering Building 1
University of Houston
4800 Calhoun Ave.
Houston, TX 77204-4004
Office Location:
Telephone:
Fax: (713) 743-4323
E-mail: vnavin "at-sign" mit "dot" edu

EDUCATION

— B.S. Chemistry, University of Madras (1998)
— M.S. Organic Chemistry, India Institute of Science (2001)
— Ph.D. Chemistry, University of Texas at Austin (2006)

RESEARCH INTERESTS

The thrust of the technologies in our lab will be aimed at developing high-throughput screens designed to characterize a wide range of functions ranging from the properties of proteins in single cells to antigen mediated cellular cytotoxicity. The development of these assays should serve as versatile platforms for the systemic investigation of B cells and antibodies in autoimmune diseases; characterizing T cell responses (CD4/CD8) in cancer and engineering therapeutic enzymes/antibodies and will lead to comprehensive programs directed towards both, vaccine development based on T cell characterization in disease states, and therapeutic intervention to target antibodies/B cells against auto-antigens in autoimmune diseases. Specifically, the three main areas of focus will be:

Characterize primary Cytotoxic T Lymphocyte (CTL) responses in cancer
The phenotype, functionality, and genetic transcriptional profile of tumor-specific CTLs capable of restricting tumor-cells in comparison to those that cannot, is currently unknown. Defining these characteristics at the single cell level will allow us to categorize the immunologic and genetic correlates that must be elicited through vaccination to drive the expansion of tumor-restrictive CD8+ T cells.

Study of autoreactive B cells/antibodies in rheumatoid arthritis
Autoimmunity towards citrulline-modified proteins underlies arthritis (at least in rodents). The adoptive transfer of monoclonal antibodies against citrullinated proteins has demonstrated a critical role for autoantibodies in the progression of arthritis. Isolating autoreactive B cells, and subsequent characterization of the autoantibodies and protein eptiopes responsible for generating these antibodies should aid both early diagnosis and therapeutic intervention in rheumatoid arthritis.

Engineering substrate specificity of proteases as a pathway for the catalytic inactivation of target proteins
Inhibitors of tumor-necrosis factor alpha (TNF-α) have shown considerable efficacy in chronic inflammatory diseases like rheumatoid arthritis. Most inhibitors are, however based on small molecules or monoclonal antibodies, and hence act in a stoichiometric manner. A catalytic inactivation approach, by modifying the substrate-specificity of human caspases to selectively hydrolyze TNF-α, will be attempted.

It is anticipated that the screening assays, once optimized in the contexts described above, can be readily adapted to addressing similar research objectives. For example, the approach that will be described for the isolation of autoantibodies in rheumatoid arthritis can also be applied to identify the mechanism, sequence and clonal diversity of naturally proteolytic antibodies in hemophilia.

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HONORS & ACTIVITIES

— 2009-Present Member, American Institute of Chemical Engineers
— 2006-Present Member, American Chemical Society
— 1998-2001 Indian Institute of Science, Integrated PhD Fellowship

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SELECTED PUBLICATIONS

1. Varadarajan N, Pogson M, Georgiou G and Iverson BL (2008) ‘Proteases that can distinguish among different post-translational forms of tyrosine engineered using multicolor flow-cytometry’ submitted J.Am.Chem.Soc.
   
2. Varadarajan N, Cantor J, Georgiou G and Iverson BL (2009) ‘Construction and flow-cytometric screening of targeted enzyme libraries’ Nature Protocols 4(6):893-901
   
3. Varadarajan N, Georgiou G, Iverson BL (2008) ‘Engineered Proteases that Cleave Specifically after Sulfalted Tyrosine for the Detection of Post-Translationally Modified Peptides’ Angew Chem Intl Ed 47(41):7861
   
4. Varadarajan N, Rodriguez S, Hwang BY, Georgiou G, Iverson BL (2008) ‘Engineering a Family of Highly Active and Selective Endopeptidases with Programmed Substrate Specificities’ Nature Chemical Biology 4(5):290-4
   
5. Hwang BY, Varadarajan N, Li H, Rodriguez S, Iverson BL, Georgiou G (2007) ‘Substrate Specificity of the Escherichia coli Outer Membrane Protease OmpP’ J. Bacteriology 189: 522-30.
   
6. Varadarajan N, Gam J, Olsen MJ, Georgiou G, Iverson BL (2005) ‘Engineering of protease variants exhibiting high catalytic activity and exquisite substrate selectivity’ Proc Natl Acad Sci U S A. 102:6855-60.
   

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