Lemira Sahar Al Ayyoubi

Research Summary

Correctors and potentiators are therapeutic drugs that correct the folding and channel gating defects of CFTR, respectively. No drugs today target the reduced stability of CFTR mutants at the apical membranes, which are caused by enhanced internalization and/or reduced recycling rates. Stability defects can be corrected by reducing the uptake, enhancing the recycling and/or reducing the lysosomal degradation of CFTR. Check out Jeanine’s and Pat’s pages for more details on CAL inhibitors developed in the Lab and which have shown stabilizing effects on the most common Δ508-CFTR mutant stability.

A large number of mutations have been identified in the chloride channel CFTR causing the genetic disease Cystic Fibrosis. CFTR regulates chloride transport across the apical membrane of epithelial cells such as in the lungs where it functions to maintain the airway surface liquid (ASL). In Cystic Fibrosis, the integrity of the ASL is compromised because of defective CFTR function resulting in the accumulation of thick mucus and the disruption of the normal mucociliary clearance of foreign pathogens, which engenders chronic bacterial and viral lung infections. Some CFTR mutations affect not only the biosynthetic processing and /or channel function, but also the half-life of CFTR at the apical membrane. I am interested in understanding the post-endocytic trafficking of CFTR, particularly the role of the CFTR-associated ligand (CAL) protein in the lysosomal degradation of internalized channels. CAL has been shown to target CFTR for lysosomal degradation and RNAi-mediated knock down of CAL in bronchial epithelial cells stabilized CFTR at the plasma membrane. My interest lies not only in understanding the basic biology of how this interplay occurs, but also to potentially identify negative regulatory proteins, such as CAL, that could be potentially used as therapeutic targets to enhance CFTR stability at the membrane in CF patients.

A number of proteins have been identified to play a role in the post-endocytic trafficking of CFTR. Clear understanding of CAL’s mode of action is still lacking.

Publications

S. Al-Ayyoubi, H. Gali-Muhtasib (2007) Differential apoptosis by gallotannin in human colon cancer cells with distinct p53 status. Mol Carcinog. 46, 176-186.

S. Al-Ayyoubi, H. Gali-Muhtasib (2007). Anti-Tumor Signaling Pathways Modulated by Plant Polyphenols. In New Cell Apoptosis Research (Valentino, R.G. ed.), Hauppauge, NY: Nova Publishers.