Andisheh Abedini

CHEMICAL BIOLOGY, BIOPHYSICAL CHEMISTRY, CELL BIOLOGY, AND PATHOPHYSIOLOGY

Our research lies at the interface of chemistry and biology. We are interested in the molecular and cellular mechanisms underlying metabolic disorders, such as diabetes and obesity, which lead to cardiovascular disease. Insufficient endogenous production of the islet β-cell derived hormones, insulin and IAPP/amylin, leads to metabolic dysregulation and diabetes. Accumulation of proteotoxic factors in the pancreatic islets of Langerhans significantly contribute to β-cell dysfunction and death, as do glucotoxicity and lipotoxicity. Identification of β-cell sparing strategies and development of better hormone replacement therapies are essential to treat metabolic disease and prevent diabetes and its complications. Our lab applies an interdisciplinary approach to investigate how proteotoxic factors activate distinct molecular mediators and cellular pathways influencing the function and fate of pancreatic islet β-cells in vitro, ex vivo and in vivo.

The fundamental goal of our work is to gain a mechanistic understanding of the role of gluco-proteotoxicity in β-cell adaptation and dysregulation in pre-diabetes and diabetes. We seek to identify critical therapeutic targets, and develop rationally designed biologics and bio-based tools to improve glycemic control and body weight management in patients with cardiometabolic disease.

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Lee, K.H., Zhyvoloup, A., Ridgway, Z., Wong, A., Eldrid, C., Hannaberry, E., Thalassinos, K., Abedini, A. and Raleigh, D. P. Analysis of baboon IAPP provides insight into amyloidogenicity and cytotoxicity of human IAPP (2020) Biophys J. 118(5):1142-1151.

Abedini, A., Cao, P., Plesner, A., Zhang, J., He, M., Derk, J., Patil, S.A., Rosario, R., Lonier, J., Song, F., Koh, H., Li, H., Raleigh, D.P., and Schmidt, A.M. RAGE binds preamyloid IAPP intermediates and mediates pancreatic β-cell proteotoxicity (2018) J. Clin. Invest. 128(2): 682-698.

Abedini, A., Derk, J., and Schmidt, A.M. The receptor for advanced glycation endproducts is a mediator of toxicity by IAPP and other proteotoxic aggregates: Establishing and exploiting common ground for novel amyloidosis therapies (2018) Protein Science 27(7): 1166-1180.

Abedini, A., Plesner, A., Cao, P., Ridgway, Z., Zhang, J., Tu, L.H., Middleton, C.T., Chao, B., Sartori, D.J., Meng, F., Wang, H., Wong, A.G., Zanni, M.T., Verchere, C.B., Raleigh, D.P. and Schmidt, A.M. Time-resolved studies define the nature of toxic IAPP intermediates, providing insight for anti-amyloidosis therapeutics (2016) eLIFE 5, pii: e12977.

Abedini, A., Cao P., Raleigh, D.P. Detection of helical intermediates during amyloid formation by intrinsically disordered polypeptides and proteins (2016) Methods Mol. Biol. 1345: 55-66.

Wang. H., Abedini, A., Ruzsicska, B.P., Raleigh, D.P. Rationally designed, non-toxic, non-amyloidogenic analogs of human islet amyloid polypeptide with improved solubility (2014) Biochemistry. 53(37): 5876-5884.

Cao, P., Abedini, A., Wang, H., Tu, L.H., Zhang, X., Schmidt, A.M., Raleigh, D.P. Islet amyloid polypeptide toxicity and membrane interactions (2013) Proc. Natl. Acad. Sci. USA 110(48): 19279-19284.

Abedini, A., Schmidt, A.M. Mechanisms of islet amyloidosis toxicity in type 2 diabetes (2013) FEBS Lett. 587(8): 1119-1127.

Meng, F., Raleigh, D.P. and Abedini, A. Combination of kinetically selected inhibitors in trans leads to highly effective inhibition of amyloid formation (2010) J. Am. Chem. Soc. 132(41):v14340-14342.

Potter, K., Abedini, A., Merek, P., Driscoll, M., Verchere, B.C. and Raleigh, D.P. Islet amyloid deposition limits the viability of human islet grafts but not porcine islet cell grants (2010) Proc. Natl. Acad. Sci. USA. 107(9): 4305-4310. Joint first authors

Abedini, A. and Raleigh, D.P. A critical assessment of the role of helical intermediates in amyloid fibril formation (2009) Protein Engineering, Design and Selection. 22(8): 453-459.

Abedini, A. and Raleigh, D.P. A role for helical intermediates in amyloid formation by natively unfolded polypeptides (2009) Physical Biology. 6(1) article ID 015005.

Abedini, A. and Raleigh, D.P. Protein Misfolding: Amyloid Formation (2008) Wiley Encyclopedia of Chemical Biology. John Wiley and Sons.

Abedini, A., Meng, F. and Raleigh, D.P. A single point mutation converts highly amyloidogenic human islet amyloid polypeptide into a potent inhibitor of fibrillization (2007) J. Am. Chem. Soc. 129(37): 11300-11301.

Abedini, A. and Raleigh, D.P. Incorporation of pseudoproline derivatives allows the facile synthesis of human IAPP; a highly amyloidogenic and aggregation-prone polypeptide (2005) Organic Letters. 7(4): 693-696.