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

Wnt/GSK3/β 连环蛋白信号传导作为双相情感障碍治疗的靶点

• 批准号: 8416603
• 负责人: Rakesh Karmacharya
• 金额: $ 9.18万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8416603
• 关键词: Wnt; GSK3; beta; Catenin; Signaling

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.

描述（由申请人提供）：拟议研究的目的是使用化学生物学方法来阐明与Wnt/GSK3/beta-catenin信号通路调节有关的新型分子机制，这与病理生理学和治疗有关躁郁症。候选人的最新工作表明，组蛋白脱乙酰基酶（HDAC）在调节β-catenin水平的调节中起作用。候选人假设特定组蛋白脱乙酰基酶同工型调节β-连环蛋白水平，并阐明β-catenin水平的HDAC调节机制，将导致对Wnt信号途径的基本理解和对新型治疗靶标的识别紊乱。 该研究建议旨在确定使用RNAi对特定的HDAC同工型以及新型的同工型特异性HDAC抑制剂来调节β-catenin水平的特定HDAC同工型。该建议旨在通过检查对染色质重塑的影响以及赖氨酸残基对β-catenin本身的影响以及乙酰化的影响，以表征β-catenin信号传导的HDAC调制机制。将对β-catenin上的赖氨酸乙酰化以及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。该提案进一步旨在研究β-catenin调节HDAC抑制剂对人神经祖细胞增殖和分化的影响。 候选人是一名医生科学家，接受了精神病学临床培训，重点是精神分裂症和躁郁症。他目前正在进行化学生物学研究后研究，重点是发现调节β-catenin信号传导的新机制。他的长期目标是建立和指导一项学术研究实验室，该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挑战。拟议的研究将在两位导师的赞助下进行：哈佛大学广泛研究所的化学生物学计划中的Stuart L. Schreiber博士，以及麦克莱恩医院的Bruce M. Cohen博士。 该奖项将支持化学生物学研究中临床知名研究的独特培训经验，并将为发现和开发双相情感障碍和精神分裂症的实验疗法建立学术途径。 公共卫生相关性：改善双相情感障碍治疗疗法仍然是一种巨大的未满足医疗需求。与现有药物相比，通过新型机制来调节WNT-GSK-3/β-catenin途径的小分子可以导致替代治疗剂的发展，与现有药物相比，具有更大功效和副作用降低。