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

描述(申请人提供)：拟议研究的目标是用化学生物学方法阐明Wnt/GSK3/β-catenin信号通路调节的新分子机制，该信号通路与双相情感障碍的病理生理和治疗有关。这位候选人最近的研究表明，组蛋白脱乙酰酶(HDAC)在调节β-连环蛋白水平方面发挥了作用。候选人假设，特异组蛋白脱乙酰酶亚型调节β-连环蛋白水平，阐明HDAC调节β-连环蛋白水平的机制(S)将有助于从根本上理解Wnt信号通路，并确定治疗双相情感障碍的新靶点。该研究计划旨在利用针对特定的HDAC亚型的RNAi以及新的针对特定亚型的HDAC抑制剂来识别调节β-连环蛋白水平的特定的HDAC亚型。该建议旨在通过检测对染色质重塑以及赖氨酸残基对β-连环蛋白本身的乙酰化的影响，来表征HDAC调节β-连环蛋白信号的潜在机制(S)。将对β-连环蛋白上的赖氨酸乙酰化以及GSK-3和酪蛋白激酶-1(CK1)的磷酸化位点进行系统的研究，以描绘磷酸化和乙酰化事件的时间和调控效应。该提案还旨在研究β-连环蛋白调节HDAC抑制剂对人神经前体细胞增殖和分化的影响。候选人是一名内科科学家，在精神病学方面接受过临床培训，重点研究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，重点是发现调控β-连环蛋白信号的新机制。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。这项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布罗德研究所化学生物学项目的斯图尔特·L·施赖伯博士和麦克莱恩医院的布鲁斯·M·科恩博士。该奖项将支持在化学生物学的临床知情研究方面的独特培训经验，并将为发现和发展双相情感障碍和精神分裂症的实验疗法奠定一条学术道路。

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.