Wnt/GSK3/beta Catenin Signaling as a Target for Treatment of Bipolar Disorder

描述（由申请人提供）：拟议研究的目标是使用化学生物学方法阐明涉及双相情感障碍病理生理和治疗的Wnt/GSK3/ β -连环蛋白信号通路调控的新分子机制。候选人最近的工作表明，组蛋白去乙酰化酶（hdac）在调节β -连环蛋白水平中起作用。候选人假设特定的组蛋白去乙酰化酶亚型调节β -连环蛋白水平，阐明HDAC调节β -连环蛋白水平的机制将导致对Wnt信号通路的基本理解，并确定双相情感障碍的新治疗靶点。该研究计划旨在鉴定调节β -连环蛋白水平的特定HDAC异构体，使用RNAi对抗特定HDAC异构体以及新型异构体特异性HDAC抑制剂。该提案旨在通过检查对染色质重塑的影响以及赖氨酸残基对β -连环蛋白本身的乙酰化，来表征HDAC调节β -连环蛋白信号传导的机制。我们将对-连环蛋白上的赖氨酸乙酰化和GSK-3和酪蛋白激酶-1 （CK1）磷酸化位点进行系统研究，以描述磷酸化和乙酰化事件的时间和调节作用。进一步研究β -连环蛋白调节HDAC抑制剂对人神经祖细胞增殖分化的影响。该候选人是一名具有精神病学临床培训的医师兼科学家，专注于精神分裂症和双相情感障碍。他目前正在进行化学生物学的博士后研究，重点是发现调节β -连环蛋白信号传导的新机制。他的长期目标是建立并指导一个学术研究实验室，将化学生物学的新策略应用于双相情感障碍和精神分裂症的临床相关挑战。拟议的研究将在两位导师的赞助下进行：哈佛大学和麻省理工学院Broad研究所化学生物学项目的Stuart L. Schreiber博士和麦克莱恩医院的Bruce M. Cohen博士。该奖项将为化学生物学临床研究提供独特的培训经验，并将为双相情感障碍和精神分裂症的实验治疗方法的发现和发展建立学术途径。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: 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.