The goal of the proposed research is to use a chemical biology approach to elucidate novel molecular mechanisms involved in the regulation of the Wnt/GSK3/beta-catenin signaling pathway, which is implicated in the pathophysiology and treatment of bipolar disorder. Recent work by the candidate showed that histone deacetylases (HDACs) play a role in modulation of beta-catenin levels. The candidate hypothesizes that specific histone deacetylase isoforms regulate beta-catenin levels and that elucidation of the mechanism(s) underlying HDAC regulation of beta-catenin levels will lead to a fundamental understanding of the Wnt signaling pathway and the identification of novel therapeutic targets for bipolar disorder. The research proposal aims to identify the specific HDAC isoforms that regulate beta-catenin levels, using RNAi against specific HDAC isoforms as well as novel isoform-specific HDAC inhibitors. The proposal aims to characterize mechanism(s) underlying HDAC modulation of beta-catenin signaling, by examining effects on chromatin remodeling as well as acetylation of lysine residues on beta-catenin itself. A systematic study of the lysine acetylation and the GSK-3 and casein kinase-1 (CK1) phosphorylation sites on beta-catenin will be conducted to delineate the temporal and regulatory effects of the phosphorylation and acetylation events. The proposal further aims to study the effects of beta-catenin modulating HDAC inhibitors on the proliferation and differentiation of human neural progenitor cells. The candidate is a physician-scientist with clinical training in psychiatry, with a focus on schizophrenia and bipolar disorder. He is currently conducting post-doctoral research in chemical biology, focusing on discovery of novel mechanisms that regulate beta-catenin signaling. His long-term goal is to establish and direct an academic research laboratory applying novel strategies in chemical biology to clinically-relevant challenges in bipolar disorder and schizophrenia. The proposed research will be carried out under the sponsorship of two mentors: Dr. Stuart L. Schreiber in the Chemical Biology Program at the Broad Institute of Harvard and MIT and Dr. Bruce M. Cohen in McLean Hospital. This award will support a unique training experience in clinically-informed research in chemical biology, and will establish an academic pathway for the discovery and development of experimental therapeutics for bipolar disorder and schizophrenia.
The development of improved therapeutics for bipolar disorder remains a significant unmet medical need. Identification of small molecules that regulate the Wnt-GSK-3/beta-catenin pathway through novel mechanims could lead to the development of alternative therapeutic agents with greater efficacy and reduced side effects compared to existing agents.
|Iaconelli, Jonathan; Lalonde, Jasmin; Watmuff, Bradley et al. (2017) Lysine Deacetylation by HDAC6 Regulates the Kinase Activity of AKT in Human Neural Progenitor Cells. ACS Chem Biol 12:2139-2148|
|Watmuff, Bradley; Berkovitch, Shaunna S; Huang, Joanne H et al. (2016) Disease signatures for schizophrenia and bipolar disorder using patient-derived induced pluripotent stem cells. Mol Cell Neurosci 73:96-103|
|Kang, Shi Hyun; Han, Hye Ree; Lee, Jong-il et al. (2015) Effects of LEP, LEPR, ADIPOQ, MC4R and FTO polymorphisms on dyslipidemia in Korean patients with schizophrenia who are taking clozapine. Psychiatry Res 228:177-8|
|Iaconelli, Jonathan; Huang, Joanne H; Berkovitch, Shaunna S et al. (2015) HDAC6 inhibitors modulate Lys49 acetylation and membrane localization of ?-catenin in human iPSC-derived neuronal cells. ACS Chem Biol 10:883-90|
|Chattopadhyay, Shrikanta; Stewart, Alison L; Mukherjee, Siddhartha et al. (2015) Niche-Based Screening in Multiple Myeloma Identifies a Kinesin-5 Inhibitor with Improved Selectivity over Hematopoietic Progenitors. Cell Rep :|
|Mehrmann, Craig; Karmacharya, Rakesh (2013) Principles and neurobiological correlates of concentrative, diffuse, and insight meditation. Harv Rev Psychiatry 21:205-18|
|England, Mary L; Ongur, Dost; Konopaske, Glenn T et al. (2011) Catatonia in psychotic patients: clinical features and treatment response. J Neuropsychiatry Clin Neurosci 23:223-6|
|Karmacharya, Rakesh; Lynn, Spencer K; Demarco, Sarah et al. (2011) Behavioral effects of clozapine: involvement of trace amine pathways in C. elegans and M. musculus. Brain Res 1393:91-9|
|Biechele, Travis L; Camp, Nathan D; Fass, Daniel M et al. (2010) Chemical-genetic screen identifies riluzole as an enhancer of Wnt/?-catenin signaling in melanoma. Chem Biol 17:1177-82|