Chemical biology of insulin-producing beta cells; Technology development
Harvard Institute of Medicine 570A
4 Blackfan Circle
Boston, MA 02115
Lab Size: 10 - 15
Our goal is to identify molecules that regenerate beta-cell mass and prevent beta-cell dysfunction and death. We also develop broadly-applicable chemical technologies with the intent of applying these technologies to specific avenues in beta cell biology. Below is a sampling of current research projects:
1) Exceptional organisms: Nature has evolved organisms that survive conditions considered pathological to humans. We are unraveling the molecular mechanisms by which infrequent feeding reptiles avert metabolic disorders despite possessing lifestyles that will be pathological to humans.
2) Chemical Technologies: Motivated by key challenges in diabetes research, we are developing the following tools/methods:
a) Next-generation genome-engineering: CRISPR-based technologies hold immense promise for therapeutic genome editing and transcriptional regulation in beta cells but suffer from several issues, including those about specificity and in vivo delivery. We are applying chemistry-based approaches to solve these issues.
b) Protein Stability in vivo: Protein misfolding and aggregation is the key driver of beta cell failure in type 2 diabetes. We are developing a general, sensitive, and label-free method that will accurately and precisely report on the changes in protein’s conformational stability and microenvironment in cellulo and in vivo.
c) Beta cell imaging and therapeutic delivery: We are developing methods for targeted delivery of therapeutic and imaging agents to the beta cells in vivo.
Maji, B., Gangopadhyay, S. A., Lee, M., Shi, M. Wu, P., Heler, R., Mok, B., Lim, D., Siriwardena, S. U., Paul, B., Dancik, V., Vetere, A., Mesleh, M. F., Marraffini, L. A., Liu, D. R., Clemons, P. A., Wagner, B. K., Choudhary, A. (2019). A high-throughput platform to identify small-molecule inhibitors of CRISPR-Cas9. Cell, 177, 1067-1079.e1019.
Maji, B, Moore, CL, Zetsche, B, Volz, S, Zhang, F, Shoulders, MD, Choudhary, A (2017). Multidimensional chemical control of CRISPR-Cas9. Nature Chemical Biology. 13, 9-11.
Cox, K. J., Subramanian, H. K. K., Samaniego, C. C., Franco, E. and Choudhary , A. (2019) A universal method for sensitive and cell-free detection of CRISPR-associated nucleases. Chemical Science, 10, 2653-2662.
Manna, D., Maji, B., Gangopadhyay, S. A., Cox, K. J., Zhou, Q., Law, B. K., Mazitschek, R., Choudhary, A. (2019). A singular system with precise dosing and spatiotemporal control of CRISPR-Cas9. Angew Chem Int Ed Engl. 58, 6285-6289.
Gangopadhyay, S. A., Cox, K. J., Manna, D., Lim, D., Maji, B., Zhou, Q., and Choudhary, A. (2019). Precision control of CRISPR-Cas9 using small molecules and light. Biochemistry, 58, 234-244.