Identification and characterization of kinase(s) responsible for androgen receptor phosphorylation at serine 16
Summary - $100,000 - "Identification and characterization of kinase(s) responsible for androgen receptor phosphorylation at serine 16" Post-translational modifications of AR have been shown to play important roles in its function, stability, and toxicity of its polyQ-expanded form. It was previously shown that blocking the N/C interaction in AR protein caused the hyperphosphorylation of a serine amino acid in the N-terminal domain of AR (serine 16, S16) and mitigated polyQ-expanded AR toxicity in mouse motor neurons. Because of the significant role of S16 phosphorylation and the therapeutic potential of kinases as viable targets for drug development, we seek to identify and validate the kinase(s) responsible for S16 phosphorylation. We have employed a combination of biochemical methods and have identified several kinases, which were specifically associated with S16. Here, we propose to investigate the role of kinase(s) that directly interact with and phosphorylate serine 16 in AR and to functionally determine the consequence of this activity in polyQ-expanded AR. This work therefore will study a novel mechanism that regulates polyQ-expanded AR toxicity and will identify potential novel targets for clinical intervention in SBMA.
Bio: Masoud Shekarabi completed his PhD at the Montreal Neurological Institute at McGill University, Canada and then carried out postdoctoral training in the laboratory of Dr. Guy Rouleau at the University of Montreal, where he investigated the roles of a specific kinase, WNK1, in the pathogenesis of both inherited sensory and peripheral neuropathy (HSANII) and agenesis of the corpus callosum with peripheral neuropathy (ACCPN, Anderman syndrome). The findings fueled a new understanding of WNK1 in pain related disorders. He has also researched HIV-1-associated neurological impairments and established an impaired dephosphorylation activity that plays a role in HIV pathogenesis. He is currently a senior researcher in the laboratory of Dr. Diane Merry at Thomas Jefferson University. He is applying his diverse skill set to understand the role of AR S16 phosphorylation in polyglutamine-expanded androgen receptor toxicity in SBMA. His long-term research goals are to study the molecular pathogenesis of neurodegenerative disorders by emphasizing the underlying mechanisms and role of kinases. By 2021, there have been 76 FDA approved small molecule protein kinase inhibitors that have reached clinical use. There are over 500 kinases in the human kinome; 182 of them are “dark kinases” which were not extensively researched and thus their roles in the disease of the nervous system are elusive.
